count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 25 10058-F4 CHEBI:149696 activates GO:0030154 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 As c-JUN, C/EBPβ, and Egr-1 have been previously implicated in monocytic differentiation, these results are consistent with the morphologic and phenotypic studies and suggest that 10058-F4 induces myeloid differentiation through activation of specific transcription factors[24–27].|||10058-F4 induces myeloid differentiation of AML cells Because c-Myc proteins regulate not only cell proliferation but also terminal differentiation of hematopoietic cells, we next examined whether 10058-F4 induces myeloid differentiation in AML cells.|||These results indicate that 10058-F4 could induce myeloid differentiation of AML cells.|||The granulocytic differentiation in HL-60 cells by 10058-F4 was not evident as measured by NBT test (data not shown), suggesting that 10058-F4 might preferentially induce monocytic differentiation.|||We also show that 10058-F4 might induce myeloid differentiation preferentially to monocytic lineage in AML cells[37].|||10058-F4 induces apoptosis and myeloid differentiation of primary leukemic cells To further demonstrate the activity of 10058-F4 on AML cells, we next tested its effects on primary AML cells from six patients and on two normal BM MNC.|||10058-F4 is likely to induce myeloid differentiation by relieving the repressive activity of c-Myc on p21.|||Because c-Myc proteins regulate not only cell proliferation but also terminal differentiation of hematopoietic cells, we next examined whether 10058-F4 induces myeloid differentiation in AML cells.|||In the mean time, 10058-F4 also induced myeloid differentiation of AML cells, possibly through modulation of specific transcription factors. 18 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 The partial reduction in apoptosis in z-DEVD-FMK–treated cells suggests that 10058-F4 induces apoptosis through both caspase-3–dependent and –independent pathways.|||As shown inFigure 6C, 10058-F4 caused apoptosis of primary AML cells from patient no.|||As apoptosis can go through either intrinsic (mitochondrial) or extrinsic (fas receptor-mediated) pathways, we next investigated through which pathway 10058-F4 induces apoptosis.|||10058-F4 induces apoptosis and myeloid differentiation of primary leukemic cells To further demonstrate the activity of 10058-F4 on AML cells, we next tested its effects on primary AML cells from six patients and on two normal BM MNC.|||10058-F4 induces cell-cycle arrest and apoptosis of AML cells We next examined whether the reduced cell numbers by 10058-F4 observed in MTT assays were caused by growth inhibition or by apoptosis.|||The release of cytoplasmic cytochrome C, upregulation of Bax, and downregulation of Bcl-2 indicate that 10058-F4 activates intrinsic pathway of apoptosis. 16 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 134ced44-bc39-11e5-ac4e-001a4ae51246 PMC4423696 At the higher concentration of 50 μm, 10058-F4 inhibited proliferation in all three groups (allp< 0.001;Fig. 3B). 8 10058-F4 CHEBI:149696 inhibits UNIPROT:P61244 Protein d8e0f092-1bce-11f0-aa93-0050569a1f61 10.1016/j.ejmech.2024.116194 Moreover, only MYCMI-6 and the previously reported 10058-F4 and 10074-G5, have been reported to selectively inhibit Myc:Max over Mad-Max (Mad1) heterodimer with no effect on other off target proteins such as Jun, a major advantage over previous inhibitors [89,92].|||Some optimistic evidence supported the idea that 10058-F4 inhibits N-Myc:Max heterodimerization along with c-Myc. 8 10058-F4 CHEBI:149696 inhibits UNIPROT:P02751 Protein 21111a66-3407-11e8-b868-001a4a160176 28483378 Western blotting demonstrated that 10058-F4 treatment inhibited the UUO-induced upregulation of fibronectin, collagen I, and α-SMA protein expression in obstructed kidneys (Figure 2a and b).|||The c-Myc inhibitor 10058-F4 attenuated fibrosis and TGF-β activation in obstructed kidneys Western blotting demonstrated that 10058-F4 treatment inhibited the UUO-induced upregulation of fibronectin, collagen I, and α-SMA protein expression in obstructed kidneys (Figure 2a and b). 8 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein d8e0f092-1bce-11f0-aa93-0050569a1f61 10.1016/j.ejmech.2024.116194 Some optimistic evidence supported the idea that 10058-F4 inhibits N-Myc:Max heterodimerization along with c-Myc.|||Moreover, only MYCMI-6 and the previously reported 10058-F4 and 10074-G5, have been reported to selectively inhibit Myc:Max over Mad-Max (Mad1) heterodimer with no effect on other off target proteins such as Jun, a major advantage over previous inhibitors [89,92]. 8 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 23092c1a-1b80-11f0-aa93-0050569a1f61 PMC7616279 The following treatments were performed:•Myc inhibition: To inhibit proliferation, cells were treated for 24 or 48 hours with the Myc inhibitor 10058-F4 (F3680, Sigma) at a final concentration of 64 μM as previously reported.43As a control, an equivalent concentration of DMSO was used.|||The lysates were snap-frozen and kept at -80°C. 3D EpiSC treatments The following treatments were performed:•Myc inhibition: To inhibit proliferation, cells were treated for 24 or 48 hours with the Myc inhibitor 10058-F4 (F3680, Sigma) at a final concentration of 64 μM as previously reported.43As a control, an equivalent concentration of DMSO was used. 8 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 13a08368-860b-11f0-afc2-0050569a791b 10.1016/j.lfs.2021.119127 As a result, a concentration of 10058-F4 higher than 30 μM increased the apoptosis rate (Fig. S7D–7E).|||Since 10058-F4 can induce cell apoptosis [28,29], we performed Annexin-V staining followed by FACS analysis to determine the apoptosis rate. 8 10058-F4 CHEBI:149696 inhibits MESH:D003094 Phenotype 21111a66-3407-11e8-b868-001a4a160176 28483378 The c-Myc inhibitor 10058-F4 attenuated fibrosis and TGF-β activation in obstructed kidneys Western blotting demonstrated that 10058-F4 treatment inhibited the UUO-induced upregulation of fibronectin, collagen I, and α-SMA protein expression in obstructed kidneys (Figure 2a and b).|||Western blotting demonstrated that 10058-F4 treatment inhibited the UUO-induced upregulation of fibronectin, collagen I, and α-SMA protein expression in obstructed kidneys (Figure 2a and b). 5 10058-F4 CHEBI:149696 activates GO:0008219 Phenotype d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 10058-F4 markedly increases the cell death induced by VPA in a caspase-dependent and -independent manner Previous studies have demonstrated that 10058-F4 efficiently induced cell death in myeloma and AML cells (15,16).|||These findings indicate that 10058-F4 dramatically increases cell death induced by VPA through caspase-dependent and -independent pathways.|||However, Z-VAD-FMK partially inhibited the cell death induced by 10058-F4 combined with VPA, indicating that their apoptotic effects involved in both caspase-dependent and -independent pathways.|||The results showed that 10058-F4 could markedly increase the cell death of Jurkat and CCRF-CEM cells induced by VPA (0, 0.8, 1.6 and 2.4 mM). 4 10058-F4 CHEBI:149696 activates UNIPROT:P08246 Protein bc2628ce-5c8b-11e7-b441-001a4ae51247 27020754 Treatment of 10058-F4 also produced more PAX6+NE cells during hESC differentiation (Figure S7K), thereby validating the data from PD0332991. 4 10058-F4 CHEBI:149696 decreases UNIPROT:P11215 Protein a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 While treatment with 10058-F4 increased expression of CD11c and CD14, and slightly decreased CD11b expression in HL-60 cells (Fig. 5A, upper panel), it increased CD14 in U937 cells and CD11b and CD14 in NB4 cells (Fig. 5B middle and lower panel). 4 10058-F4 CHEBI:149696 inhibits UNIPROTPRO:PRO:0000032458 Protein 21111a66-3407-11e8-b868-001a4a160176 28483378 Consistent with the effects of 10058-F4,c-MycsiRNA inhibited the Ang II–induced accumulation of ECM proteins including fibronectin, collagen I, and α-SMA (Figure 6c). 4 10058-F4 CHEBI:149696 inhibits UNIPROT:P04198 Protein d8e0f092-1bce-11f0-aa93-0050569a1f61 10.1016/j.ejmech.2024.116194 Some optimistic evidence supported the idea that 10058-F4 inhibits N-Myc:Max heterodimerization along with c-Myc. 4 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 Treatment with 10058-F4 decreased levels of c-Myc proteins in all three cell lines (Fig. 2A). 4 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein 4378b07c-04df-11f0-bb39-0050569a791b 10.1016/j.bcp.2024.116065 The c-Myc inhibitor, 10058-F4, decreased c-Myc levels but had relatively no effect on Bcl-xL and Bim protein levels (Fig. 6F&G). 4 10058-F4 CHEBI:149696 activates GO:0006351 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 As lineage specification of hematopoietic cells is determined by activation of unique sets of transcription factors, we next used quantitative real-time reverse transcription PCR to examine whether 10058-F4 activates specific transcription factors during myeloid differentiation of HL-60 cells. 4 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 We next investigated whether 10058-F4 inhibits cell proliferation through downregulation of cyclins. 4 10058-F4 CHEBI:149696 inhibits MESH:D009369 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 Because 10058-F4 has been shown to inhibit cell growth of solid tumors, we next determined its activity on AML cell by MTT assays[14]. 4 10058-F4 CHEBI:149696 activates GO:0051320 Phenotype 13a08368-860b-11f0-afc2-0050569a791b 10.1016/j.lfs.2021.119127 Thus, the S-phase arrest induced by 10058-F4 or c-Myc overexpression might result from dysregulated activity of KLF5 (Fig. S6). 4 10058-F4 CHEBI:149696 inhibits GO:0007049 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 We found that 10058-F4 did not affect levels of cyclin D1 and cyclin D3 (data not shown), but markedly decreased levels of cyclin D2 (Fig. 3C), suggesting that 10058-F4 is likely to arrest cell cycle through inhibition of specific binding of c-Myc to cyclin D2 promoter. 4 10058-F4 CHEBI:149696 activates MESH:D008697 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 As shown inFigure 6C, 10058-F4 caused apoptosis of primary AML cells from patient no. 4 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype b5eeaaa6-d4aa-11ea-9fa3-001a4a160175 PMC7378318 Cell growth was attenuated by 50 μM 10058-F4, 200 nM gemcitabine, and 50 or 25 μM betulin (Figures 4A–4E), with or without insulin cotreatment. 4 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 Because 10058-F4 has been shown to inhibit cell growth of solid tumors, we next determined its activity on AML cell by MTT assays[14]. 4 10058-F4 CHEBI:149696 inhibits FPLX:TGFB ProteinFamily 21111a66-3407-11e8-b868-001a4a160176 28483378 The upregulation of TGF-β, phosphorylated Smad2 (p-Smad2), and phosphorylated Smad3 (p-Smad3) in the obstructed kidneys indicated TGF-β signaling activation, which was also inhibited by 10058-F4 treatment. 4 10058-F4 CHEBI:149696 inhibits UNIPROT:O14593 Protein 0a12cb5e-338d-11e8-9fbf-001a4a160176 16410134 Inhibitor concentration curves by MTT assays confirmed that 100 μmol/L of 10058-F4 completely impaired the growth of the LCL and BLs at 72 hours (data not shown).|||Effect of c-Myc inhibitor on c-Myc RNA levels Inhibitor concentration curves by MTT assays confirmed that 100 μmol/L of 10058-F4 completely impaired the growth of the LCL and BLs at 72 hours (data not shown). 4 10058-F4 CHEBI:149696 decreases UNIPROT:Q2M3G0 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 Furthermore, 10058-F4 treatment and the combined 5-FU and 10058-F4 treatment decreased the ABCB5 expression level when compared with the control (Fig.6Gand H).|||As expected, 10058-F4 treatment decreased ABCB5 expression at mRNA and protein levels (Fig.4Band C).|||As expected, 10058-F4 treatment decreased the ABCB5 expression level in spite of the presence or the absence of 5-FU treatment. 4 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype b8feefd4-390b-11e8-9192-001a4a160175 25443862 Apoptosis was induced by 50-100uM 10058-F4 in all cell lines[40,41].|||It is reported that 10058-F4 induces apoptosis through down-regulation of Bcl-2, Bcl-xL and up-regulation of caspase-3 in AML cells[14]. 4 UNIPROT:P84022 inhibits 10058-F4 CHEBI:149696 Protein 21111a66-3407-11e8-b868-001a4a160176 28483378 Ang II also upregulated TGF-β and the activation of downstream smad2 and smad3 signaling, which was also inhibited by pretreatment with 10058-F4 (Figure 5d and e). 4 UNIPROT:Q15796 inhibits 10058-F4 CHEBI:149696 Protein 21111a66-3407-11e8-b868-001a4a160176 28483378 Ang II also upregulated TGF-β and the activation of downstream smad2 and smad3 signaling, which was also inhibited by pretreatment with 10058-F4 (Figure 5d and e). 3 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 induces apoptosis To verify that 10058-F4 treatment inhibits cell proliferation by inducing apoptosis, we investigated apoptotic cells by applying an Annexin-V and PI double staining assay after a 24 hours treatment.|||However, the 8 primary cultures that had achievable IC50 values showed an increase in different levels of caspase-3 activity, suggesting that the ability of 10058-F4 to inhibit cell proliferation in primary cultures may be mainly dependent on the induction of apoptosis.Table 1Pathologic features and inhibition of cell growth by 10058-F4 in primary culture cells of ovarian carcinomaPatient IDAGEDiagnosisStageGradeIC50 (uM)c-MYCavb65SerousIIIAG127PositiveOC272SerousIIICG384PositiveOC348SerousIIAG128PositiveOC436SerousICG156PositiveOC566SerousIIIAG126PositiveOC661MucousIIIAG2>100PositiveOC755SerousIIICG3NPositiveOC851SerousIIAG362PositiveOC969SerousIIICG3>100PositiveOC1053SerousIIIAG130PositiveOC1138MucousIAG1>100PositiveOC1247SerousIIICG3NPositiveOC1364MucousIIIAG118PositiveOC1466SerousIIICG3NPositiveOC1562SerousIIIAG2>100PositiveOC1657SerousIIIAG122PositiveOC1743SerousIIAG333PositiveOC1851SerousIIICG316Positive18 primary culture cells of ovarian cancer were cultured in 96 well plates or 6 well plates and treated with 10058-F4 as indicated doses. 3 10058-F4 CHEBI:149696 decreases UNIPROT:Q8TCG1 Protein 4047539a-c470-11e5-8491-001a4ae51247 19470954 "As shown inFigure 7, C, 10058-F4 treatment efficiently inhibited CIP2A expression in thymidine/aphidicolin–treated cells.|||The rapid time course of 10058-F4–elicited inhibition of CIP2A mRNA expression suggests that MYC directly affects CIP2A transcription.|||As shown inFigure 6, A, treatment of AGS cells with the concentration range (60–100 μM) of 10058-F4 that has previously been shown to inhibit MYC-mediated gene regulation (60–120 μM) (26,27) potently inhibited CIP2A mRNA expression." 3 10058-F4 CHEBI:149696 inhibits MESH:D009369 Phenotype 6e987f55-f58a-11eb-949b-001a4a160176 30503555 The results indicated that Sorafenib, Regorafenib, 2-DG, BPTES or 10058-F4 could inhibit the tumor growth of PDX models (Fig. 7d and Additional file 9:Fig. S9).|||Interestingly, we observed that 2-DG, BPTES or 10058-F4 could only synergize with Sorafenib or Regorafenib to repress PDX#6 tumor growth, but not in the PDX#9 group.|||c-Myc shRNA or 10058-F4 could also largely abolish the promoting effect of Gankyrin on the growth of subcutaneous and orthotopic hepatic tumors formed by HuH-7  3 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 370f81b0-c486-11e5-9da3-001a4ae51247 22806891 Apoptosis was induced by 50-100μM 10058-F4 in all cell lines expressing c-MYC, whereas the U266 cell line, which does not express c-MYC, was only minimally sensitive at 100μM (Figure 1B).|||This finding is consistent with the proposal that 10058-F4 is a specific inhibitor of c-MYC–MAX heterodimerization at concentrations < 100μM.7,8Forced expression of L-MYC12in INA-6 cells did not counteract apoptosis induced by 10058-F4 (supplemental Figure 2).|||INA-6 cells were equally sensitive to apoptosis induced by 10058-F4 in the presence and absence of MM-derived BMSCs (Figure 2A). 2 10058-F4 CHEBI:149696 increases UNIPROT:P07333 Protein 682c72f4-d43e-11e5-b157-001a4ae51247 PMC4509841 We found that Myc and M-CSFR expression were induced during culture of cells with M-CSF (Fig. 5f and 5g), and inhibition of Myc with the compound 10058-F4 suppressed induction of M-CSFR expression (Fig. 5g), suggesting that Myc is required for M-CSFR expression and mTORC1 activity in macrophages. 2 10058-F4 CHEBI:149696 inhibits UNIPROT:Q13794 Protein 0856a4bc-bc38-11e5-9b9d-001a4ae51247 PMC3504066 The results showed that 10058-F4 partially repressed V1801-induced Noxa up-regulation (Fig. 4e) and cytotoxicity in NCI-H1975 cells (Fig. 4f). 2 10058-F4 CHEBI:149696 increases UNIPROT:P53985 Protein e2f35f76-ab1a-11e6-b3b6-001a4ae51247 PMC5046889 Luciferase reporter activity in SW480 (f), SW620 (g), and DLD1 (h) cells shows that treatment with the Wnt inhibitor XAV939 (10 μM) and increasing concentrations of c-Myc inhibitor 10058-F4 decrease transcription of the SLC16A1 promoter additively, but not synergistically. 2 10058-F4 CHEBI:149696 inhibits UNIPROT:O95139 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 CI=(D)1/(Dx)1+(D)2/(Dx)2, where (Dx)1 and (Dx)2 indicate the individual dose of ATO/Vincristine and 10058-F4 required to inhibit a given level of viability index, and (D)1 and (D)2 are the doses of ATO/Vincristine and 10058-F4 necessary to produce the same effect in combination, respectively. 2 10058-F4 CHEBI:149696 activates UNIPROT:P38936 Protein a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 We also show that upregulation of p21 by 10058-F4 is p53-independent, consistent with the loss of p53 function in these cell lines[30,31]. 2 10058-F4 CHEBI:149696 increases UNIPROT:P04198 Protein 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 While 10074-G5 decreased the MYCN protein levels at lower concentrations than 10058-F4, the putative metabolite C-m/z232 showed only a slight reduction in the MYCN levels at high concentrations, and the 10058-F4 analogs #474 and #764 did not cause any changes in the MYCN protein levels at the concentrations which were possible to use without apoptosis induction (Figure 4). 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 7fc7814a-c473-11e5-91a7-001a4ae51247 PMC4420226 10058-F4 significantly decreased both c-Myc (P=0.005) (Figure 1A) and c-Myc S62 (P=0· 2 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 10058-F4 is likely to induce myeloid differentiation by relieving the repressive activity of c-Myc on p21. 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 These results support the hypothesis that 10058-F4 inhibits c-Myc activity through specific inhibition of its DNA binding activity. 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein b8feefd4-390b-11e8-9192-001a4a160175 25443862 10058-F4, a small-molecule inhibitor, has been identified to inhibit c-MYC-MAX heterodimerization, thereby preventing transactivation of c-Myc target genes[38,39]. 2 10058-F4 CHEBI:149696 inhibits GO:0010467 Phenotype 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 Similar results were observed in C4-2 cells, where 10058-F4 inhibited ligand-independent and DHT-stimulated AR target gene expression (Fig. 5D, left), and decreased AR and Myc transcript (Fig. 5D, right). 2 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 21111a66-3407-11e8-b868-001a4a160176 28483378 Ang II–induced activation and proliferation of renal fibroblasts was suppressed by 10058-F4 Western blotting revealed that both the protein and mRNA levels of c-Myc increased significantly after Ang II treatment for 48 hours (Figure 5a and b). 2 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 13a08368-860b-11f0-afc2-0050569a791b 10.1016/j.lfs.2021.119127 10058-F4 treatment rescues cell cycle progression and cell proliferation in H2BL-L3P overexpression cells Since treatment with 30 μM 10058-F4 for 3 days seemed to over rescue cell proliferation (Fig. S7A), we hypothesized that treatment with 20 μM 10058-F4 would partly rescue cell proliferation and cell cycle distribution, while treatment with 40 μM 10058-F4 would over rescue these phenotypes. 2 10058-F4 CHEBI:149696 inhibits MESH:D018417 Phenotype 12db271c-d431-11e5-90d3-001a4ae51247 PMC4729201 10058-F4 can also inhibit Th1 and Th17 developmentin vitroand 10058-F4 treated mice were resistant to EAE developmentin vivo(Bandukwala et al., 2012). 2 10058-F4 CHEBI:149696 activates GO:0007049 Phenotype 13a08368-860b-11f0-afc2-0050569a791b 10.1016/j.lfs.2021.119127 10058-F4 treatment rescues cell cycle progression and cell proliferation in H2BL-L3P overexpression cells Since treatment with 30 μM 10058-F4 for 3 days seemed to over rescue cell proliferation (Fig. S7A), we hypothesized that treatment with 20 μM 10058-F4 would partly rescue cell proliferation and cell cycle distribution, while treatment with 40 μM 10058-F4 would over rescue these phenotypes. 2 10058-F4 CHEBI:149696 activates MESH:D005355 Phenotype 21111a66-3407-11e8-b868-001a4a160176 28483378 The c-Myc inhibitor 10058-F4 attenuated fibrosis and TGF-β activation in obstructed kidneys Western blotting demonstrated that 10058-F4 treatment inhibited the UUO-induced upregulation of fibronectin, collagen I, and α-SMA protein expression in obstructed kidneys (Figure 2a and b). 2 10058-F4 CHEBI:149696 activates MESH:D000255 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Thus 10058-F4 reduced ROS generation and inhibited cellular ATP production, implicating the relevance of ROS presence and ATP reduction in the cytotoxicity of 10058-F4 in ovarian carcinoma cells. 2 10058-F4 CHEBI:149696 inhibits GO:0030154 Phenotype 32c2fde6-bc32-11e5-ac4e-001a4ae51246 PMC3827269 Recently it was shown that MYC protein levels decrease during the differentiation and that MYC inhibitor 10058-F4, by disturbing the formation of functional MYC/MAX heterodimer, leads to differentiation and induction of germ layer markers in hESCs[22]. 2 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 Effect of small-molecules on growth inhibition and apoptosis in MYCN-amplified cells The small molecules 10058-F4, 10074-G5, as well as #474 inhibit cell proliferation and induce apoptosis in a variety of c-MYC expressing cells[28],[33],[34],[39], and we have shown that 10058-F4 induces apoptosis and inhibits cell growth in MYCN overexpressing NB cells[40]. 2 10058-F4 CHEBI:149696 dephosphorylatesProtein FPLX:RNApo:II ProteinFamily 23b45f04-bbe0-11e5-9b9d-001a4ae51247 10.1016/j.stem.2011.06.010 One piece of evidence is the finding that addition of high concentrations of 10058-F4 inhibits phosphorylation of RNA polymerase II at serine 2, a hallmark of elongating RNA polymerase. 2 10058-F4 CHEBI:149696 inhibits FPLX:Cyclin ProteinFamily a872efbc-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.06.019 In agreement with prior studies that c-Myc directly activates cyclin D2 by binding to the E-box in its promoter, we show that 10058-F4 specifically downregulated cyclin D2 but not cyclin D1 or D3[23]. 2 10058-F4 CHEBI:149696 decreases UNIPROT:P10275 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 Interestingly, AR expression, which is stabilized through DHT-mediated receptor dimerization (39), was decreased by 10058-F4 in both androgen-depleted and DHT-stimulated conditions (compare lanes 1 with 2 and 3 with 4).|||Treatment with 10058-F4 Myc inhibitor similarly decreases Myc expression and attenuates AR expression and activity, suggesting that within this model of prostate cancer, Myc expression and/or activity is requisite for productive AR signaling. 2 10058-F4 CHEBI:149696 decreases UNIPROT:Q07820 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 increased cleaved PARP, caspase3 and caspase7 protein expression(F and G)and decreased BCL-2 and MCL-1 protein expression(H).|||In addition, we found 10058-F4 reduced BCL-2 and MCL-1 protein expression in a dose dependent manner after treatment of 10058-F4 for 24 hours (Figure3E-H). 2 10058-F4 CHEBI:149696 decreases UNIPROT:O15440 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 Although 10058-F4 treatment decreased ABCC5 expression, it appeared that the decrease in ABCC5 expression had no effect on 5-FU resistance because of its low expression in COLO-320 cells.|||Although 10058-F4 treatment decreased ABCC5 expression, the expression level of ABCC5 protein was very low in COLO-320 cells (Fig.4D, upper panel). 2 10058-F4 CHEBI:149696 decreases UNIPROT:Q8TCG1 Protein 7fc7814a-c473-11e5-91a7-001a4ae51247 PMC4420226 In High CIP2A patients treatment with 10058-F4 significantly reduces CIP2A protein levels to a greater degree than observed with imatinib (Figure 2G).|||In patients with a high diagnostic CIP2A level, 10058-F4 significantly reduced c-Myc (P=0.03) (Figure 2A) and CIP2A protein levels (P=0· 2 10058-F4 CHEBI:149696 inhibits UNIPROT:Q8TCG1 Protein 8df9fd94-bbe3-11e5-8abe-001a4ae51246 PMC3782751 "We then compared expression of Hk2 with that of Cyclin D2, a marker of Shh-induced proliferation, and Cip2A, a known myc target previously demonstrated to be inhibited by 10058-F4 [28,29].|||We found 10058-F4 reduced Shh-mediated induction of Hk2, Cip2A and Cyclin D2 in a dose-dependent manner (Figure4C)." 2 10058-F4 CHEBI:149696 decreases UNIPROT:Q14568 Protein a520afa8-bc52-11e5-8d2d-001a4ae51247 PMC2841080 In addition, treatment with c-Myc inhibitor 10058-F4 or siRNA experiments to repress the endogenous HSP90alpha levels in HBx-expressing cells decreased their invasion activity (Figure4).|||Moreover, the increased expression of HSP90alpha in the presence of HBx could be completely inhibited by treatment with c-Myc inhibitor 10058-F4 or introducing a specific-siRNA (Figure2C). 2 10058-F4 CHEBI:149696 decreases UNIPROT:P10415 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 In addition, we found 10058-F4 reduced BCL-2 and MCL-1 protein expression in a dose dependent manner after treatment of 10058-F4 for 24 hours (Figure3E-H).|||10058-F4 increased cleaved PARP, caspase3 and caspase7 protein expression(F and G)and decreased BCL-2 and MCL-1 protein expression(H). 2 10058-F4 CHEBI:149696 decreases UNIPROT:P11309 Protein 1a9776fe-bc44-11e5-8abe-001a4ae51246 PMC2886047 Pim1 mRNA levels were not dramatically changed after inhibitor treatment (Figure8B), suggesting that 10058-F4 may inhibit Pim1 protein levels via post-translational regulation in addition to c-MYC transcriptional activity.|||Remarkably, 10058-F4 also repressed both the endogenous human and transgenic murine Pim1 protein expression in both cell lines (Figure8B). 2 10058-F4 CHEBI:149696 activates UNIPROT:P22735 Protein b51de0ba-ae95-11ec-840e-0050569a791b PMCPMC8163689 Topical application of 10058-F4 to the wounds of diabetic rats (DM+10058-F4) also prevented the decrease of TGM1 (Figure 4C), LOR (Figure 4D) and K1 (Figure 4E) in keratinocytes at the wound margin as shown in the DM group.|||Similarly, 10058-F4 prevented the decrease of TGM1, LOR and K1 caused by high glucose (Figure 4B). 2 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 7c9d5eae-ae96-11ec-89b1-0050569a791b PMCPMC8718798 Immunofluorescent staining also showed that IL-18 promoted the nuclear expression of c-MYC, while 10058-F4 significantly reduced the nuclear expression of c-MYC that was induced by IL-18 (Figure 6E).|||Compared to the control group, 10058-F4 and sic-MYC significantly reduced the expression of c-MYC at the mRNA and protein levels, with expression of c-MYC reduced, it’s also reduced the expression of SLC7A5,ALP,BMP2 and RUNX2; however, IL-18 treatment partially restored the bone formation ability in 10058-F4 and sic-MYC groups (Figures 6A–D). 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 65cfba3c-7920-11e8-a34c-001a4a160176 PMC6102154 "Conversely, when c-Myc is inhibited by 10058-F4 or siRNAs, this may block alternative activation of macrophages and in turn suppressLeishmaniasurvival (Fig. 7,AandB).|||Similarly, inhibition of c-Myc by 10058-F4 led to a 10-fold reduction in parasite counts (Fig. 7B)." 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 7c9d5eae-ae96-11ec-89b1-0050569a791b PMCPMC8718798 Moreover, IL-18 reversed the downregulation of c-MYC and osteogenic markers induced by siRNA and the c-MYC specific inhibitor 10058-F4, indicating that IL-18 plays a role via c-MYC regulation (Figure 6).|||To further investigate whether the inhibition of c-MYC can reverse the IL-18-induced osteogenic differentiation of hBMSCs, cells were treated with c-MYC antagonists 10058-F4 and sic-MYC to inhibit c-MYC expression. 2 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 1a9776fe-bc44-11e5-8abe-001a4ae51246 PMC2886047 This phenomenon, where 10058-F4 treatment reduces MYC protein levels in some cell types but not others, even though it inhibits MYC activity in both types of cells, has been noted previously [40,41].|||Interestingly, 10058-F4 inhibited c-MYC expression itself in LNCaP cells as shown previously but not in DU145 cells (Figure8B). 2 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 Treatment with 10058-F4 Myc inhibitor similarly decreases Myc expression and attenuates AR expression and activity, suggesting that within this model of prostate cancer, Myc expression and/or activity is requisite for productive AR signaling.|||Myc mRNA expression was decreased by 10058-F4, which coincided with reduced AR mRNA. 2 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein eaaaae32-bbdc-11e5-9b9d-001a4ae51247 10.1016/j.ccr.2013.01.026 To confirm that 10058-F4 indeed inhibited c-Myc function in these cells, we measured the abundance of mRNAs for cyclin D2 and ornithine decarboxylase 1 (ODC1), the genes for which are direct targets of c-Myc.|||The abundance of these mRNAs was increased in Fbxw7-deficient LICs compared with that in control cells, and each increase was attenuated by 10058-F4, suggesting that 10058-F4 indeed inhibits c-Myc activity in these cells (Figure 3C). 2 10058-F4 CHEBI:149696 activates UNIPROT:P23490 Protein b51de0ba-ae95-11ec-840e-0050569a791b PMCPMC8163689 Topical application of 10058-F4 to the wounds of diabetic rats (DM+10058-F4) also prevented the decrease of TGM1 (Figure 4C), LOR (Figure 4D) and K1 (Figure 4E) in keratinocytes at the wound margin as shown in the DM group.|||Similarly, 10058-F4 prevented the decrease of TGM1, LOR and K1 caused by high glucose (Figure 4B). 2 10058-F4 CHEBI:149696 decreases UNIPROT:Q9UNQ0 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 ABCG2 was expressed in COLO-320 cells at protein level, and 10058-F4 treatment did not decrease ABCG2 expression.|||ABCG2 protein was expressed in COLO-320 cells, and 10058-F4 treatment did not decrease ABCG2 expression (Fig.4D, middle panel). 2 10058-F4 CHEBI:149696 activates CHEBI:45783 Chemical a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 10058-F4 potentiated Imatinib anti-proliferative properties and disrupt the cell cycle distribution.|||To clarify the molecular mechanisms through which 10058-F4 potentiates the efficacy of Imatinib, qRT-PCR was performed to examine the expression levels of genes involved in regulating cell transition. 2 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Assessment of apoptosis using flow cytometry Annexin-V/PI staining was applied to investigate whether 10058-F4 as a single agent could induce apoptotic cell death in acute leukemia cell lines.|||Lin et al. showed that 10058-F4 induces an apoptotic cell death in a panel of hepatocellular carcinoma cell lines through activation of mitochondrial pathway (Lin et al., 2007). 2 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype e67ce7d6-8dee-11e7-a20e-001a4ae51247 27406986 transplanted human Panc1 cells, but 10058-F4 synergistically induced apoptosis together with gemcitabine (35).|||10058-F4 interacts with the amino acids 402–409 of the C-terminal bHLH-LZ domain of MYC (34), thereby preventing MYC/MAX dimerization.In vitro, 10058-F4 was shown to impair proliferation and to induce apoptosis of human PDAC cells (35). 2 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 However, the 8 primary cultures that had achievable IC50 values showed an increase in different levels of caspase-3 activity, suggesting that the ability of 10058-F4 to inhibit cell proliferation in primary cultures may be mainly dependent on the induction of apoptosis.Table 1Pathologic features and inhibition of cell growth by 10058-F4 in primary culture cells of ovarian carcinomaPatient IDAGEDiagnosisStageGradeIC50 (uM)c-MYCavb65SerousIIIAG127PositiveOC272SerousIIICG384PositiveOC348SerousIIAG128PositiveOC436SerousICG156PositiveOC566SerousIIIAG126PositiveOC661MucousIIIAG2>100PositiveOC755SerousIIICG3NPositiveOC851SerousIIAG362PositiveOC969SerousIIICG3>100PositiveOC1053SerousIIIAG130PositiveOC1138MucousIAG1>100PositiveOC1247SerousIIICG3NPositiveOC1364MucousIIIAG118PositiveOC1466SerousIIICG3NPositiveOC1562SerousIIIAG2>100PositiveOC1657SerousIIIAG122PositiveOC1743SerousIIAG333PositiveOC1851SerousIIICG316Positive18 primary culture cells of ovarian cancer were cultured in 96 well plates or 6 well plates and treated with 10058-F4 as indicated doses.|||Results results 10058-F4 inhibits cell proliferation and colony formation To investigate the potential inhibition of cell growth by 10058-F4 in ovarian cancer, we first examined the effect of 10058-F4 on cell proliferation and clonogenic survival in SKOV3 and Hey cells. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P10275 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 Similar results were observed in C4-2 cells, where 10058-F4 inhibited ligand-independent and DHT-stimulated AR target gene expression (Fig. 5D, left), and decreased AR and Myc transcript (Fig. 5D, right). 1 10058-F4 CHEBI:149696 activates UNIPROT:P08865 Protein 2c855470-bc45-11e5-ac4e-001a4ae51246 PMC2835723 Moreover, treatment of cells with 10058-F4 increased SA β-gal activity, indicating that c-MYC activity is a pivotal regulator of MSC senescence (Figure S6C). 1 10058-F4 CHEBI:149696 activates UNIPROT:P11274 Protein a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 Given the effectiveness of 10058-F4 in several types of leukemia and to enhance the efficiency of CML treatment, we investigated the stimulatory effects of the c-Myc inhibition on the anti-leukemic effects of Imatinib in CML-derived K562 and NALM-1 cells. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P11274 Protein a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 The results obtained from the synergistic experiments outlined that treatment of K562 with 10058-F4 and Imatinib remarkably diminished the survival and metabolic activity of CML cells compared to either agent alone. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:Q13309 Protein 9ee2880c-eeb9-11e5-9b35-001a4ae51246 23792459 At the transcriptional level, 10058-F4 (60 μM) effectively decreased SKP2 mRNA accumulation and promoter activity in both melanoma cells (Figure 3g). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P11169 Protein f28fbc48-c865-11ee-b346-0050569a791b 10.1016/j.bbrc.2023.03.051 Treatment of HNOA cells with 10058-F4, a MYC inhibitor, abolished OA-induced upregulation ofGLUT1,GLUT3, andGLUT4(Fig. 5B). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:Q9NZC3 Protein d4031ef8-bbdc-11e5-9b9d-001a4ae51247 PMC4369817 Our results demonstrated that treatment with either 10058-F4 or cryptotanshinone prevented the down-regulation of miR-16 induced by treatment with PE (Fig.5C). 1 10058-F4 CHEBI:149696 decreases UNIPROT:Q92833 Protein 8b1ecbe6-8d8c-11e7-a9fb-001a4ae51247 PMC5485424 However, combinations of PLX4032 or GSK1120212 and 10058-F4 dramatically downregulated Jarid2 expression in both BCPAP and K1 cells. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P36871 Protein bd7c8644-c86a-11ee-9133-0050569a1f61 10.1016/j.bbrc.2023.03.034 What's more, 10058-F4 treatment can even decrease PGM1 expression at both mRNA (Fig. 4H) and protein (Fig. 4I) levels under the low glucose condition. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P36871 Protein bd7c8644-c86a-11ee-9133-0050569a1f61 10.1016/j.bbrc.2023.03.034 When we detected the activity of PGM1 promoter via luciferase reporter assay, we found that 10058-F4 treatment could obviously decrease the PGM1 promoter activity (Fig. 4J). 1 10058-F4 CHEBI:149696 decreases UNIPROT:Q07817 Protein 370f81b0-c486-11e5-9da3-001a4ae51247 22806891 Bcl-xL expression was down-regulated by 10058-F4 in INA-6, but not in the U266 cell line. 1 10058-F4 CHEBI:149696 activates UNIPROT:P16893 Protein 9e0dcbc8-bbf9-11e5-8abe-001a4ae51246 PMC4249944 Similar to I-BET151 treatment, the MYC inhibitor 10058-F4 suppressed TNF-induced serum TRAP (Fig. 5i) and significantly reduced both osteoclast surface area per bone surface (OcS/BS) and osteoclast numbers per bone surface (NOc/BS) (Fig. 5j). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P07288 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 As shown, DHT stimulation increased PSA, FKBP5, and Myc transcripts, and 10058-F4 decreased ligand-independent PSA expression and DHT-induced PSA and FKBP5 (Fig. 5C). 1 10058-F4 CHEBI:149696 activates UNIPROT:P61244 Protein db460dbc-8d8e-11e7-bc62-001a4ae51247 PMC5533867 With this approach it was demonstrated that 10058-F4 and 10074-G5 caused an unfolding of the c-Myc/Max coiled-coil dimer into disordered monomeric states. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P61244 Protein 0c050144-bc2e-11e5-8d2d-001a4ae51247 PMC4286170 "For example, melatonin has been shown to interfere with the apoptotic pathway by impeding the dimerization of the pro-apoptotic protein BAX (the interacting partner of BCL2).113Also, the small molecule 10058-F4, known to bind to the C-terminal domain of MYC, inhibits a family of transcriptional factors including c-MYC, MYCN, and MAX." 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P61244 Protein f1880d4a-5c1b-11e7-8b40-001a4ae51247 PMC5442404 To quantify the contributions of c-MYC and β-catenin on regulation ofPHBtranscription, we analyzed transcript level ofPHBin Raji cells with treatment by 10058-F4, a c-myc inhibitor, that disrupts formation of the c-MYC/MAX heterodimer. 1 10058-F4 CHEBI:149696 activates UNIPROT:P61244 Protein 517ecb62-bc4f-11e5-8abe-001a4ae51246 10.1016/j.chembiol.2008.09.011 The addition of 10058-F4 to the heterodimer led to complete disordering of c-Myc and Max. 1 10058-F4 CHEBI:149696 activates UNIPROT:P61244 Protein d1281fea-c47d-11e5-9cc6-001a4ae51246 PMC2993546 "In vitro, 10058-F4 exhibited high binding affinity to the bHLH-ZIP domain of c-Myc, promoted dissociation of the c-Myc/Max dimer, prevented binding of the heterodimer to DNA targets, induced cell cycle arrest, and caused apoptosis (Yin et al., 2003;Gomez-Curet et al., 2006;Huang et al., 2006;Lin et al., 2007;Sampson et al., 2007;Wang et al., 2007;Follis et al., 2008)." 1 10058-F4 CHEBI:149696 increases UNIPROT:P04629 Protein e9524aa2-49dc-11e6-81ee-001a4ae51246 27396325 We found that DEX moderately increased TrkA whereas 10058-F4 led to a more-robust TrkA expression, both alone and in combination with DEX (Figures 5F and 5G). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:O00499 Protein 3ea317f4-ae93-11ec-8f68-0050569a1f61 PMCPMC8704450 Interestingly, the small molecule MYC-specific inhibitor 10058-F4 [39,40] was sufficient to increase the BIN1-Luc activity in the CDDP-R cells. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P42574 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Pretreatment with Z-VAD-FMK resulted in total blocking of 10058-F4 induced caspase-3 activity and a significant decrease in the inhibition of 10058-F4-mediated proliferation in both cells (Figure3I and J), suggesting that inducing mitochondrial apoptosis may be a major mechanism to inhibit cell proliferation in 10058-F4 treated ovarian cancer cells. 1 10058-F4 CHEBI:149696 activates UNIPROT:P42574 Protein d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 In addition, western blot analysis revealed that 10058-F4 could promote the cleavage of caspase-3 induced by VPA (Fig. 4B). 1 10058-F4 CHEBI:149696 decreases PR:000036819 Protein f5f4b78a-5801-11e6-81ee-001a4ae51246 PMC4965757 10058-F4 (50 μM) markedly suppressed the amount of core protein, as well as c-Myc, PDK1, and PDK3 protein levels (Supplementary Fig. S4a). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P11166 Protein 44178d4e-c72f-11ee-ae05-0050569a1f61 10.1016/j.celrep.2023.113306 10058-F4 treatment also reversed the upregulation of Glut1 (Figure 7D) and increased the positive percentage of MitoSOX in activated CD226-deficient Treg cells (Figure 7E). 1 10058-F4 CHEBI:149696 activates UNIPROT:Q12778 Protein 76d0ed1a-bc12-11e5-9b9d-001a4ae51247 PMC4645183 10058-F4 abrogated the pro-osteoclastogenesis effect of FOXO1 inhibition in RAW264.7 cells (Fig. 7C,D) in a dose dependent manner. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P31314 Protein b60bd7e0-bc41-11e5-ac4e-001a4ae51246 PMC2913983 Compound 10058-F4 treatment decreased the growth of ALL-SIL cells to similar levels regardless of TLX1 expression (Figure4A), suggesting that augmentation of MYC function is a central mechanism of TLX1 contribution to ALL-SIL cell growth. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P00259 Protein 6e987f55-f58a-11eb-949b-001a4a160176 30503555 The results indicated that Sorafenib, Regorafenib, 2-DG, BPTES or 10058-F4 could inhibit the tumor growth of PDX models (Fig. 7d and Additional file 9:Fig. S9). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:Q14568 Protein a520afa8-bc52-11e5-8d2d-001a4ae51247 PMC2841080 Treatment of the HBx-expressing cells with the c-Mycspecific inhibitor 10058-F4 resulted in a significantly decreased of both mRNA and protein levels of HSP90alpha (Figure2Band2C), suggesting that 10058-F4 blocked the induction of HSP90alpha activation by HBx. 1 10058-F4 CHEBI:149696 increases UNIPROT:O43490 Protein 0a18b708-c486-11e5-a92e-001a4ae51246 PMC3497809 "We showed that a MYC inhibitor, 10058-F4, suppressed MYCN expression, CD133 expression, and SCD and caused ACD in a neuroblastoma cell line." 1 10058-F4 CHEBI:149696 phosphorylatesProtein UNIPROT:O60674 Protein 8c08bd42-c465-11e5-8491-001a4ae51247 PMC3935234 "The MYC inhibitor 10058-F4 (28) also reduced the survival and proliferation of glioblastoma multiforme cells, and reduced Jak2 expression and Stat3 phosphorylation (Fig. 4K and L)." 1 10058-F4 CHEBI:149696 increases UNIPROT:O60674 Protein 8c08bd42-c465-11e5-8491-001a4ae51247 PMC3935234 "The MYC inhibitor 10058-F4 (28) also reduced the survival and proliferation of glioblastoma multiforme cells, and reduced Jak2 expression and Stat3 phosphorylation (Fig. 4K and L)." 1 10058-F4 CHEBI:149696 increases UNIPROT:P48436 Protein d953c80a-c810-11ee-b346-0050569a791b 10.1016/j.drup.2023.100976 The treatment of cells with the c-Myc inhibitor 10058-F4 could significantly reduce SOX9 expression, and abolished the effect of CD73 overexpression on promoting lenvatinib resistance (Ma et al., 2020a). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:Q5VV67 Protein 35833626-ab16-11e6-8a7c-001a4ae51246 PMC5207252 "2A, increasing concentrations of 10058-F4 inhibited the induction of both PRC and c-MYC by CCCP without affecting NRF-2α expression, demonstrating that c-MYC is required for the induction of PRC." 1 10058-F4 CHEBI:149696 decreases UNIPROT:P12004 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 The combined treatment of 5-FU and 10058-F4 tended to decrease the Ki67-positive ratio and to increase the TUNEL-positive ratio the most.In vitrostudy also showed that the combined treatment of 5-FU and 10058-F4 increased the ratio of Annexin V- and PI-positive cells and decreased the expression level of PCNA (Fig. S2AandB). 1 10058-F4 CHEBI:149696 increases UNIPROT:P38936 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Consistently, evaluating the impact of the inhibitor on the mRNA expression level of the critical genes responsible for the transition of the cells from G1 to S phase also revealed that 10058-F4 increased the mRNA expression level of p21, p27, and p15 in wild-type p53 expressing Nalm-6 cells (Fig. 4B). 1 10058-F4 CHEBI:149696 increases UNIPROT:P42772 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Consistently, evaluating the impact of the inhibitor on the mRNA expression level of the critical genes responsible for the transition of the cells from G1 to S phase also revealed that 10058-F4 increased the mRNA expression level of p21, p27, and p15 in wild-type p53 expressing Nalm-6 cells (Fig. 4B). 1 10058-F4 CHEBI:149696 increases UNIPROT:P46527 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Consistently, evaluating the impact of the inhibitor on the mRNA expression level of the critical genes responsible for the transition of the cells from G1 to S phase also revealed that 10058-F4 increased the mRNA expression level of p21, p27, and p15 in wild-type p53 expressing Nalm-6 cells (Fig. 4B). 1 10058-F4 CHEBI:149696 increases UNIPROTPRO:PRO:0000008516 Protein b465fa6c-f595-11eb-978f-001a4a160176 31712778 As expected, the c-Myc inhibitor, 10058-F4, downregulated CD47 mRNA and surface protein expression in Hut78 and HH cells (Fig.1e). 1 10058-F4 CHEBI:149696 increases UNIPROT:P04637 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Consistently, evaluating the impact of the inhibitor on the mRNA expression level of the critical genes responsible for the transition of the cells from G1 to S phase also revealed that 10058-F4 increased the mRNA expression level of p21, p27, and p15 in wild-type p53 expressing Nalm-6 cells (Fig. 4B). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P04637 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Although it is early to hazard a conjecture on the mechanism by which 10058-F4 reduced the viability of mutant p53-expressing NB4 cells, a possible candidate would be NF-κB, a key cellular transcription factor that engages in a cross-talk with c-Myc (La Rosa et al., 1994). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P10415 Protein a89f6234-bc41-11e5-8abe-001a4ae51246 PMC4216870 10058-F4 can decrease BCL2 protein levels [28]; BCL2 and other anti-apoptotic BCL2 proteins confer antiestrogen resistance in breast cancer cells [29]. 1 10058-F4 CHEBI:149696 increases UNIPROT:O43524 Protein 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Noteworthy, the results of RQ-PCR showed that 10058-F4 not only elevated the mRNA expression level of FOXO3a in Nalm-6 but not NB4 cells, but also shifted the ratio of the death promoter to death repressor genes via alteration of Bax and Bcl-2 expression. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:O00139 Protein 8df9fd94-bbe3-11e5-8abe-001a4ae51246 PMC3782751 We found 10058-F4 reduced Shh-mediated induction of Hk2, Cip2A and Cyclin D2 in a dose-dependent manner (Figure4C). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P31350 Protein 9999f1d6-c485-11e5-9cc6-001a4ae51246 PMC3346129 Progesterone-induced RRM2 expression is inhibited by either 10058-F4 or UCN-01. 1 10058-F4 CHEBI:149696 increases UNIPROT:P21589 Protein d953c80a-c810-11ee-b346-0050569a791b 10.1016/j.drup.2023.100976 The treatment of cells with the c-Myc inhibitor 10058-F4 could significantly reduce SOX9 expression, and abolished the effect of CD73 overexpression on promoting lenvatinib resistance (Ma et al., 2020a). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P21589 Protein d953c80a-c810-11ee-b346-0050569a791b 10.1016/j.drup.2023.100976 The treatment of cells with the c-Myc inhibitor 10058-F4 could significantly reduce SOX9 expression, and abolished the effect of CD73 overexpression on promoting lenvatinib resistance (Ma et al., 2020a). 1 10058-F4 CHEBI:149696 increases UNIPROT:P24522 Protein a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 Of note, while Imatinib and 10058-F4 could elevate the expression of GADD45A, the combination of these agents elevated the expression of this molecule more vigorously. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P19338 Protein 8b1ecbe6-8d8c-11e7-a9fb-001a4ae51247 PMC5485424 Moreover, 10058-F4 dramatically downregulated the expression of Ncl, a downstream target of c-Myc27, suggesting that transcriptional activity of c-Myc was inhibited by 10058-F4. 1 10058-F4 CHEBI:149696 phosphorylatesProtein UNIPROT:P40763 Protein 8c08bd42-c465-11e5-8491-001a4ae51247 PMC3935234 "The MYC inhibitor 10058-F4 (28) also reduced the survival and proliferation of glioblastoma multiforme cells, and reduced Jak2 expression and Stat3 phosphorylation (Fig. 4K and L)." 1 10058-F4 CHEBI:149696 decreases UNIPROT:P06703 Protein b51de0ba-ae95-11ec-840e-0050569a791b PMCPMC8163689 Furthermore, overexpression ofc-Mycor high glucose caused a significant increase in S100A6 protein levels, which was abolished by 10058-F4 treatment. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P35226 Protein 2c855470-bc45-11e5-ac4e-001a4ae51246 PMC2835723 Additionally, BMI1 expression was decreased by 10058-F4 treatment in hUCB- and hAD-MSCs in a time-dependent fashion (Figure S6D), suggesting that inhibition of c-MYC activity precedes the downregulation of BMI1 expression in MSC senescence. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P04198 Protein e9524aa2-49dc-11e6-81ee-001a4ae51246 27396325 Treatment with 10058-F4 reduced MYCN levels (Figures 5A and 5D;Zirath et al., 2013), whereas GR expression was upregulated, which is consistent with an inverse relationship between MYCN and GR (Figures 5A and 5E). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P04198 Protein 2428e5ca-c475-11e5-a92e-001a4ae51246 PMC4571491 Interestingly, U266 cells, which have low c-MYC expression (3), were sensitive to MI1-PD and MI1, at higher molar exposures, corroborating reports that 10058-F4 can inhibit n-MYC (34, 35). 1 10058-F4 CHEBI:149696 increases UNIPROT:P04198 Protein 0a18b708-c486-11e5-a92e-001a4ae51246 PMC3497809 "We showed that a MYC inhibitor, 10058-F4, suppressed MYCN expression, CD133 expression, and SCD and caused ACD in a neuroblastoma cell line." 1 10058-F4 CHEBI:149696 increases UNIPROT:P04198 Protein e9524aa2-49dc-11e6-81ee-001a4ae51246 27396325 As expected, 10058-F4 induced a decrease in MYCN levels with a concomitant upregulation in GR (Figures 5J–5L). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P04198 Protein 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 In summary, only 10058-F4 and 10074-G5 were able to efficiently decrease the MYCN protein levels. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P04198 Protein 0a18b708-c486-11e5-a92e-001a4ae51246 PMC3497809 "As expected, 10058-F4 down-regulated MYCN expression in TGW cells (Fig. S8A)." 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P04198 Protein 0c050144-bc2e-11e5-8d2d-001a4ae51247 PMC4286170 "For example, melatonin has been shown to interfere with the apoptotic pathway by impeding the dimerization of the pro-apoptotic protein BAX (the interacting partner of BCL2).113Also, the small molecule 10058-F4, known to bind to the C-terminal domain of MYC, inhibits a family of transcriptional factors including c-MYC, MYCN, and MAX." 1 10058-F4 CHEBI:149696 increases UNIPROT:Q2M3G0 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 c-MYC inhibitor, 10058-F4, decreased the ABCB5 expression level through the inhibition of c-MYC binding to theABCB5promoter It is well known that c-MYC protein oncogenic activity requires dimerization with MAX24. 1 10058-F4 CHEBI:149696 increases UNIPROT:Q9H6T0 Protein dee6ceae-c70a-11ee-b346-0050569a791b 10.1016/j.bcp.2023.115848 The Myc inhibitor 10058-F4 suppresses the expression of ESRP2 (epithelial splicing regulatory protein 2); the CLK inhibitor SM08502 is shown to decrease SRSFs phosphorylation[78,66]. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P08922 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 decreases Reactive Oxygen Species (ROS) and ATP generation Reactive Oxygen Species (ROS) are required for ovarian cancer cell growth [17]. 1 10058-F4 CHEBI:149696 activates UNIPROT:P08922 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Thus 10058-F4 reduced ROS generation and inhibited cellular ATP production, implicating the relevance of ROS presence and ATP reduction in the cytotoxicity of 10058-F4 in ovarian carcinoma cells. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:O14746 Protein afac0a50-5c1d-11e7-af4d-001a4ae51247 PMC5406870 Moreover, 10058-F4 also downregulated human telomerase reverse transcriptase expression and abrogated telomerase activity [79]. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 2c855470-bc45-11e5-ac4e-001a4ae51246 PMC2835723 To further assess the role of c-MYC in MSC senescence, a chemical inhibitor of c-MYC, 10058-F4, was used in hUBC- and hAD-MSCs. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 7eeecce4-c7d8-11ee-9aaa-0050569a1f61 10.1016/j.biopha.2023.114926 Moreover, inhibition of c-Myc by 10058-F4 treatment effectively lowered both systolic and diastolic BP with decrease of renal Agt expression induced by HFD. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 20705430-bc2e-11e5-8d2d-001a4ae51247 PMC3888240 Myc inactivation by siRNA or 10058-F4 abrogated the increased ER stress in SIRT7 KD cells (Figures 4K andS3I). 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein 1419a0a4-c8e7-11e5-9ad8-001a4ae51247 17876039 4Cand as described previously (18), 10058-F4 caused a reduction in total c-Myc levels. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 35833626-ab16-11e6-8a7c-001a4ae51246 PMC5207252 "2A, increasing concentrations of 10058-F4 inhibited the induction of both PRC and c-MYC by CCCP without affecting NRF-2α expression, demonstrating that c-MYC is required for the induction of PRC." 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 370f81b0-c486-11e5-9da3-001a4ae51247 22806891 Apoptosis was induced by 50-100μM 10058-F4 in all cell lines expressing c-MYC, whereas the U266 cell line, which does not express c-MYC, was only minimally sensitive at 100μM (Figure 1B). 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein b4aee7ea-f2e7-11e8-9dc2-001a4a160175 PMC6294174 For this, we conducted cell reprogramming experiments in the presence or absence of the MYC inhibitor 10058-F4 (ic-MYC), known to impair endogenous MYC biological activity (Scognamiglio et al., 2016). 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein ac80b7ca-bc52-11e5-8abe-001a4ae51246 PMC3384945 However, addition of the c-Myc inhibitor 10058-F4, which disrupts the conformation of the c-Myc protein, to mimic BIN1-mediated inhibition of c-Myc was 25% less effective than full-length BIN1-expressing cells in inducing cisplatin sensitivity in an Annexin V-binding assay. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 6e987f55-f58a-11eb-949b-001a4a160176 30503555 Further results indicated that c-Myc pathway inhibition by shRNA or 10058-F4 greatly reduced the promoting effect of Gankyrin on anchorage-independent cell growth of HuH-7  1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 4123ba84-c9b6-11ee-b346-0050569a791b 10.1016/j.ejmech.2022.114779 Current strategies targeting c-Myc in cancer include 10058-F4, 10074-G5, and JY-3-094, which could prevent c-Myc from adopting the conformation for dimerization with Max [28–30], or inhibiting c-Myc/Max dimerization for binding to DNA, such as Mycro 3 and KJ-Pyr-9 [31,32]. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 35833626-ab16-11e6-8a7c-001a4ae51246 PMC5207252 "Thus, both the pharmacological inhibition of c-MYC by 10058-F4 and c-MYC siRNA silencing are consistent with a requirement for c-MYC for the induction of PRC and the PRC stress genes by CCCP." 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 8df9fd94-bbe3-11e5-8abe-001a4ae51246 PMC3782751 "We then compared expression of Hk2 with that of Cyclin D2, a marker of Shh-induced proliferation, and Cip2A, a known myc target previously demonstrated to be inhibited by 10058-F4 [28,29]." 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 Similar results were observed in C4-2 cells, where 10058-F4 inhibited ligand-independent and DHT-stimulated AR target gene expression (Fig. 5D, left), and decreased AR and Myc transcript (Fig. 5D, right). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 The present study results showed that 10058-F4 and VPA synergistically downregulated c-Myc expression in Jurkat and CCRF-CEM cells. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein b3baf85c-f575-11eb-8418-001a4a160175 32203166 To block the role of c-Myc, the cells were treated with 100 μM 10058-F4 (Houston, TX, USA, cat#s7153), an inhibitor of c-Myc, for 48 h before harvest. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 2f55e662-c89c-11ee-9aaa-0050569a1f61 10.1016/j.ijpharm.2023.122865 In addition, Che-Pin Lin and co-workers demonstrated that c-MYC inhibition by 10058-F4, a small-molecule c-MYC inhibitor, enhances the chemosensitivity of tumor cells to low-doses of chemotherapeutic agents (Lin et al., 2007). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 5c27d460-c730-11ee-b346-0050569a791b 10.1016/j.jep.2023.116625 4F, JQZF inhibited the proliferation of Raji cells more significantly after 10058-F4 inhibited the expression of c-Myc, compared with the MO+10058-F4 group (P <0.05). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein f1880d4a-5c1b-11e7-8b40-001a4ae51247 PMC5442404 To quantify the contributions of c-MYC and β-catenin on regulation ofPHBtranscription, we analyzed transcript level ofPHBin Raji cells with treatment by 10058-F4, a c-myc inhibitor, that disrupts formation of the c-MYC/MAX heterodimer. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 8791ed9a-37e9-11e6-8a17-001a4ae51247 PMC4820680 This effect could be dose dependent and/or due to cell-specific degradation of inactive MYC as previous studies have shown that 10058-F4 induces a dose-dependent reduction in MYC expression in some cell types.33,34 ITGB1, the only partner of ITGA1 to form the integrin α1β1, contains the cognate CACGTG E-box in its proximal promoter.37MYCN reduces ITGB1 expression in neuroblastoma cells,38but MYC regulation of ITGB1 in intestinal epithelial cells has not been reported. 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein 5ca21206-bc1d-11e5-8abe-001a4ae51246 PMC2656245 Similarly, pretreatment with the c-Myc inhibitor 10058-F4 unexpectedly decreased c-Myc expression and interrupted the phosphorylation of ERK1/2 induced by TGFβ1 (Figure8c). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 0a18b708-c486-11e5-a92e-001a4ae51246 PMC3497809 Subsequently, it was reported that 10058-F4 decreased both levels of bothMYCmRNA (45%) and MYC protein (50%) expression to the endogenous levels (28). 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 Thus, we hypothesized that 10058-F4 promotes the downregulation of c-Myc expression induced by VPA. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 2a4c711e-ae94-11ec-8b2e-0050569a1f61 PMCPMC8507273 The luciferase reporter gene assay showed that the c-Myc transactivation activity of H1299 cells was suppressed by 10058-F4 from 10 μM to 50 μM (Figure 5B). 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 10058-F4 treatment decreased the amount of c-MYC binding to theABCB5promoter (Fig.4A). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 0c050144-bc2e-11e5-8d2d-001a4ae51247 PMC4286170 "For example, melatonin has been shown to interfere with the apoptotic pathway by impeding the dimerization of the pro-apoptotic protein BAX (the interacting partner of BCL2).113Also, the small molecule 10058-F4, known to bind to the C-terminal domain of MYC, inhibits a family of transcriptional factors including c-MYC, MYCN, and MAX." 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein f640f39a-aa75-11e6-b510-001a4ae51247 PMC5105131 Inhibitor of c-myc (10058-F4) was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 229b4680-ae93-11ec-a61d-0050569a1f61 PMCPMC8216717 Moreover, inhibition of c-Myc activity by 10058-F4 (Yin et al., 2003; Figure 5D) or knocking down c-Myc with siRNAs (Figure 5E) significantly reduced the mRNA abundance of Smpdl3b in WT mESCs but not or to a less extend in SIRT1 KO mESCs, indicating that c-Myc is a key transcription factor in SIRT1-mediated regulation of Smpdl3b. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 20342dc2-bc36-11e5-9b9d-001a4ae51247 PMC4551852 The agent 10058-F4 (5-[(4-ethylphenyl)methylene]-2-thioxo-4-thiazolidinone) was used to abolish the transactivating ability of MYC. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 1419a0a4-c8e7-11e5-9ad8-001a4ae51247 17876039 4A, 10058-F4, as well as all tested analogues, promoted the dissociation of c-Myc from Max in this assay. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein bc2226cc-bbf4-11e5-8abe-001a4ae51246 10.1016/j.exphem.2011.05.002 On the other hand, although 10058-F4 exerted the dose-dependent effect on c-Myc protein level, and treatment with >60 μM 10058-F4 for 24 hours suppressed c-Myc expression as was reported previously[20,21], we found no correlation between the cell death−inducing effect of 10058-F4 and expression levels of c-Myc (Fig. 5C, D). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 20705430-bc2e-11e5-8d2d-001a4ae51247 PMC3888240 Myc inactivation by siRNA or 10058-F4 abrogated the increased ER stress in SIRT7 KD cells (Figures 4K andS3I). 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein d5a797f2-bbdc-11e5-8abe-001a4ae51246 PMC4511355 c-MYC inhibitor, 10058-F4, decreased the amount of c-MYC binding to its binding site within theABCB5promoter region and led to the decrease in ABCB5 expression at mRNA and protein levels. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein d51de4fa-5c1f-11e7-af4d-001a4ae51247 PMC5387383 To explore the role of the RBM38-mediated decrease in c-Myc expression in the RBM38-induced suppression of breast cancer, the specific c-Myc inhibitors, 10058-F4 and 10074-G5, were used to repress the transcriptional activity of c-Myc. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein b60bd7e0-bc41-11e5-ac4e-001a4ae51246 PMC2913983 In retrospect, since the majority of NOTCH-induced genes in T-ALL are also targeted by MYC [58], it is perhaps not surprising to find that virtually all of the TLX1/NOTCH signature genes that we validated by qRT-PCR negatively responded to inhibition of MYC by compound 10058-F4 treatment. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein ed6ea61c-c7ab-11ee-9133-0050569a1f61 10.1016/j.gene.2023.147571 Treatment of cells with c-MYC/MAX inhibitor, 10058-F4, reduced the expression of c-MYC target genes, whereas, the non-target genes were unaffected by the treatment. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 5ca21206-bc1d-11e5-8abe-001a4ae51246 PMC2656245 10058-F4 downregulates c-Myc expression and ERK1/2 phosophorylation The c-Myc inhibitor 10058-F4 we used was isolated by Yinet al. [21] using a yeast two-hybrid system. 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein ed80e84c-c6af-11ee-9aaa-0050569a1f61 10.1016/j.celrep.2023.113434 In contrast, BBOX1 expression was downregulated in BxPC-3 through SERPINB3 knockout or treatment with a MYC inhibitor (10058-F4) at both mRNA and protein levels (Figures 7L–7N), confirmingBBOX1as a target gene of MYC. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 is known specifically to inhibit the c-Myc-Max interaction, decrease c-Myc protein expression, and prevent transactivation of c-Myc target genes [9,10]. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein d1281fea-c47d-11e5-9cc6-001a4ae51246 PMC2993546 "In vitro, 10058-F4 exhibited high binding affinity to the bHLH-ZIP domain of c-Myc, promoted dissociation of the c-Myc/Max dimer, prevented binding of the heterodimer to DNA targets, induced cell cycle arrest, and caused apoptosis (Yin et al., 2003;Gomez-Curet et al., 2006;Huang et al., 2006;Lin et al., 2007;Sampson et al., 2007;Wang et al., 2007;Follis et al., 2008)." 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein c4c8113e-ab80-11e6-9ac8-001a4ae51246 PMC4815801 Therefore, we investigated whether the activation of caspases could be diminished by inhibition of c-Myc using 10058-F4, a selective Myc-Max inhibitor (Huanget al, 2006). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein ac2ea270-bc19-11e5-9b9d-001a4ae51247 PMC4027186 The inhibitory effect of 10058-F4 that prevents conversion of Myc to its DNA-binding form (heterodimer with Max) suggests that Myc might bind to binding sites within the rDNA IGS (Figure5A). 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 517ecb62-bc4f-11e5-8abe-001a4ae51246 10.1016/j.chembiol.2008.09.011 The addition of 10058-F4 to the heterodimer led to complete disordering of c-Myc and Max. 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 As we expected, 10058-F4 treatment for 36 hours induced a marked decrease in the protein expression of c-Myc in a dose-dependent manner in both cell lines when compared to the control group (Figure1C and D). 1 10058-F4 CHEBI:149696 increases UNIPROT:P01106 Protein 5343d200-1f53-11e6-ae18-001a4ae51246 PMC5173084 To assess the direct effect of blocking c-Myc on glutamine metabolism we used the c-Myc inhibitor 10058-F4, which inhibits the c-Myc-Max interaction and prevents transactivation of c-Myc target gene expression. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P01106 Protein b51de0ba-ae95-11ec-840e-0050569a791b PMCPMC8163689 In addition, 10058-F4 is reported to inhibit the expression of c-Myc protein in a dose-dependent manner (37,38). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:P01106 Protein 1ad4d146-5ccc-11e7-86a3-001a4ae51246 PMC4685021 To determine whether 10058-F4–mediated Myc inhibition impinges on AR signaling, thus phenocopying ABC294640 treatment and representing a mechanism for Myc and AR inactivation, cells were cultured in androgen-deprived media and stimulated with dihydrotestosterone (DHT) and/or 10058-F4. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein 396e5f88-19d3-11e6-ae18-001a4ae51246 PMC5216924 The prolonged G2 phase in 10058-F4 treated cells was comparable to the effect of αIgM treatment alone and thus supports the inverse correlation of BCR.1 and the Myc index shown in Figure5A/B. 1 10058-F4 CHEBI:149696 activates UNIPROT:P01106 Protein db460dbc-8d8e-11e7-bc62-001a4ae51247 PMC5533867 With this approach it was demonstrated that 10058-F4 and 10074-G5 caused an unfolding of the c-Myc/Max coiled-coil dimer into disordered monomeric states. 1 10058-F4 CHEBI:149696 decreases UNIPROT:P04626 Protein d113575a-ede4-11e5-872c-001a4ae51246 PMC4560624 "In this study, a combination of 10058-F4 and trastuzumab reduced tamoxifen-resistant tumor burden by downregulating HER2 expression." 1 10058-F4 CHEBI:149696 activates UNIPROT:P15692 Protein 936b1596-ae95-11ec-840e-0050569a791b PMCPMC8093282 We show that 10058-F4 significantly increased the endogenous VEGF-A a/VEGF-A b ratio in PC3 and podocyte cells, resulting in anti-angiogenic properties ex vivo.ESSO8 – GW2974 – is a potent and selective dual EGFR and ErbB-2 receptor tyrosine kinase inhibitor. 1 10058-F4 CHEBI:149696 increases UNIPROT:P07101 Protein e9524aa2-49dc-11e6-81ee-001a4ae51246 27396325 Importantly, both DEX and 10058-F4 stimulated an increase in TH expression, which was further enhanced when both compounds were used together (Figures 5J and 5M). 1 10058-F4 CHEBI:149696 activates UNIPROT:O75832 Protein 6e987f55-f58a-11eb-949b-001a4a160176 30503555 Importantly, we observed that c-Myc inhibitor (10058-F4) also largely abolished the promoting effects of Gankyrin on glycolysis and glutaminolysis (Additional file 3:Fig. S3). 1 10058-F4 CHEBI:149696 inhibits UNIPROT:O75832 Protein 6e987f55-f58a-11eb-949b-001a4a160176 30503555 c-Myc shRNA or 10058-F4 could also largely abolish the promoting effect of Gankyrin on the growth of subcutaneous and orthotopic hepatic tumors formed by HuH-7  1 10058-F4 CHEBI:149696 increases UNIPROT:O15235 Protein cc7b507a-cbd6-11ee-9aaa-0050569a1f61 10.1016/j.jff.2015.09.030 The c-Myc inhibitor 10058-F4 and two RPS12 shRNAs were used to reduce RPS12 expression and analyse the effect on the invasion of cancer cells. 1 10058-F4 CHEBI:149696 activates UNIPROT:O15235 Protein cc7b507a-cbd6-11ee-9aaa-0050569a1f61 10.1016/j.jff.2015.09.030 The c-Myc inhibitor 10058-F4 significantly reduced the transactivation activity of the RPS12 promoter. 1 10058-F4 CHEBI:149696 inhibits CHEBI:90524 Chemical f7713e44-3360-11e8-9192-001a4a160175 24140475 Interestingly, a cMyc inhibitor (10058-F4) also increased the effectiveness of PI-103[30]. 1 10058-F4 CHEBI:149696 activates CHEBI:17234 Chemical 58110618-3900-11e8-8636-001a4a160175 26211592 Given that c-Myc regulates the expression of several glycolytic enzymes including hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), we hypothesize that whether 10058-F4 enhances GEM chemosensitivity in PDAC through regulating glycolytic enzymes expression and glucose utilization. 1 10058-F4 CHEBI:149696 inhibits CHEBI:17234 Chemical 2386cc41-f58b-11eb-94cd-001a4a160176 30771425 4g and h, Myc overexpression restored the decreased lactate production and glucose consumption of FGF13-AS1-transfected cells, whereas 10058-F4 inhibited lactate secretion and glucose consumption to a comparable degree as FGF13-AS1 in MDA-MB-231  1 10058-F4 CHEBI:149696 decreases CHEBI:24996 Chemical 482d3320-c8b5-11ee-b346-0050569a791b 10.1016/j.intimp.2023.109985 5B, treatment with 10058-F4 could effectively decrease the secretion of lactate induced by TGF-β1. 1 10058-F4 CHEBI:149696 decreases CHEBI:85045 Chemical 8b1ecbe6-8d8c-11e7-a9fb-001a4ae51247 PMC5485424 Similar to thein vitrofindings,in vivodata showed that 10058-F4 dramatically decreased the levels of PRC2 components and H3K27me3 inTPO-Cre/LSL-BrafV600Emice (Figure5C). 1 10058-F4 CHEBI:149696 inhibits CHEBI:45783 Chemical a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 c-Myc inhibition using 10058-F4 enhanced Imatinib-induced anti-proliferative properties in K562 cell. 1 10058-F4 CHEBI:149696 inhibits CHEBI:33390 Chemical 2a4c711e-ae94-11ec-8b2e-0050569a1f61 PMCPMC8507273 Moreover, the pretreatment of 10058-F4 could suppress the CM of LDR promoted cell migration (Figure 5Eand5F). 1 10058-F4 CHEBI:149696 inhibits CHEBI:44658 Chemical f28fbc48-c865-11ee-b346-0050569a791b 10.1016/j.bbrc.2023.03.051 These observations were consistent with the findings that OA enhancement of [3H]-2-DG uptake was attenuated by 10058-F4 and (+)-JQ-1 (Fig. 5D). 1 10058-F4 CHEBI:149696 activates CHEBI:16467 Chemical 6d937e0e-f53c-11eb-acf4-001a4a160175 29248687 Moreover, the pAdEasy-FOXG1 andc-Myc inhibitor 10058-F4 abolished the effect of L-Arg on the number of double-BrdU and PCNA-positive cells in the regenerated epidermis. 1 10058-F4 CHEBI:149696 activates CHEBI:175901 Chemical e67ce7d6-8dee-11e7-a20e-001a4ae51247 27406986 transplanted human Panc1 cells, but 10058-F4 synergistically induced apoptosis together with gemcitabine (35). 1 10058-F4 CHEBI:149696 activates CHEBI:151 Chemical a89f6234-bc41-11e5-8abe-001a4ae51246 PMC4216870 MYC inhibition induces apoptosis and cell cycle in resistant cells To determine how 10058-F4 restored sensitivity of LCC9 cells to ICI, we studied changes in apoptosis. 1 10058-F4 CHEBI:149696 activates CHEBI:68647 Chemical 6e987f55-f58a-11eb-949b-001a4a160176 30503555 Interestingly, we observed that 2-DG, BPTES or 10058-F4 could only synergize with Sorafenib or Regorafenib to repress PDX#6 tumor growth, but not in the PDX#9 group. 1 10058-F4 CHEBI:149696 inhibits MESH:D015452 Phenotype 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 The results obtained in the present study showed that 10058-F4 effectively reduced the survival and proliferative capacity of both pre-B ALL-derived Nalm-6 and APL-derived NB4 cells; however, the anti-leukemic effect of the inhibitor in deficient PTEN-expressing Nalm-6 cells were achieved at the higher concentrations as compared to NB4 cells harboring wild-type PTEN. 1 10058-F4 CHEBI:149696 inhibits GO:0046722 Phenotype 2386cc41-f58b-11eb-94cd-001a4a160176 30771425 4g and h, Myc overexpression restored the decreased lactate production and glucose consumption of FGF13-AS1-transfected cells, whereas 10058-F4 inhibited lactate secretion and glucose consumption to a comparable degree as FGF13-AS1 in MDA-MB-231  1 10058-F4 CHEBI:149696 inhibits GO:0006351 Phenotype 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 We found that 10058-F4 could apparently decrease transcription of the anti-apoptotic target genes of NF-κB in APL-derived NB4 cells; however, analyzing the effect of the inhibitor on molecular feature of less sensitive Nalm-6 cells unraveled the inaptitude of 10058-F4 on NF-κB modulation. 1 10058-F4 CHEBI:149696 inhibits MESH:D006528 Phenotype 2324e5d6-bbd1-11e5-956b-001a4ae51247 PMC3161244 One such small molecule, 10058-F4, inhibited the growth of hepatocellular carcinoma cells in vitro (Lin et al., 2007). 1 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 16d306be-b286-11ee-bde4-0050569a1f61 10.1038/s41388-020-1222-7 Moreover, inhibition of c-MYC with 10058-F4 in NIH3T3/C1orf35 can slow down cell proliferation rates (Fig.S1). 1 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 Effect of small-molecules on growth inhibition and apoptosis in MYCN-amplified cells The small molecules 10058-F4, 10074-G5, as well as #474 inhibit cell proliferation and induce apoptosis in a variety of c-MYC expressing cells[28],[33],[34],[39], and we have shown that 10058-F4 induces apoptosis and inhibits cell growth in MYCN overexpressing NB cells[40]. 1 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 412195ac-37be-11e6-b56c-001a4ae51246 PMC4877299 Similar to EGFR inhibitors, 10058-F4 reduces proliferation of KrasG12Dexpressing PDECs, supporting an important function of MYC downstream of the EGFR. 1 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 7fc7814a-c473-11e5-91a7-001a4ae51247 PMC4420226 10058-F4 also significantly reduced the rate of cellular proliferation (P=0.003), (Figure 1F). 1 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype 5ca21206-bc1d-11e5-8abe-001a4ae51246 PMC2656245 By contrast, pretreatment with either 10058-F4, a c-Myc, inhibitor or PD98059, an ERK1/2 inhibitor, arrested cell proliferation and cell cycle progression when coexistent with TGFβ1 (Figures3,4,5,6). 1 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype a69952d6-c96e-11ee-ae05-0050569a1f61 PMC10404563 The MYC inhibitor 10058-F4 also inhibited nodule formation, proliferation, and lipid accumulation in mutant HEPs (Figure 9A and B). 1 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Together, these results demonstrate suppressive effects of 10058-F4 on the proliferation of ovarian cancer cells.Figure 110058-F4 inhibits cell proliferation in ovarian cancer cells.SKOV3 and Hey cells were cultured for 24 hours and treated with F4-10058 as indicated doses in 96 well plates for 72 hours. 1 10058-F4 CHEBI:149696 inhibits GO:0008283 Phenotype e67ce7d6-8dee-11e7-a20e-001a4ae51247 27406986 10058-F4 interacts with the amino acids 402–409 of the C-terminal bHLH-LZ domain of MYC (34), thereby preventing MYC/MAX dimerization.In vitro, 10058-F4 was shown to impair proliferation and to induce apoptosis of human PDAC cells (35). 1 10058-F4 CHEBI:149696 activates GO:0008283 Phenotype 58110618-3900-11e8-8636-001a4a160175 26211592 Results c-Myc inhibitor, 10058-F4, inhibits cell proliferation, induces cell apoptosis and enhances chemosensitivity of PDAC cells to GEM To observe the potential inhibition effect of 10058-F4 in PDAC, we first measured the IC50 value of 10058-F4 in PANC-1 and SW1990 cells by CCK8 assay. 1 10058-F4 CHEBI:149696 activates MESH:D009369 Phenotype b3c33760-bbda-11e5-9b9d-001a4ae51247 PMC4675788 These findings could have therapeutic implications since combination treatment of tumor xenografts of tamoxifen resistant breast cancer cells, BT474, with a MYC inhibitor (10058-F4) and HER2 inhibitor (Trastuzumab) significantly reduced tumor growth in immunodeficient NSG mice (Figure1). 1 10058-F4 CHEBI:149696 inhibits MESH:D009369 Phenotype 43242672-3b4e-11e8-8636-001a4a160175 29466695 10058-F4 also suppressed the growth of neuroblastoma tumors in TH-MYCN-driven transgenic mice andMYCN-amplified neuroblastoma cells grown as xenografts in nude mice [72,73]. 1 10058-F4 CHEBI:149696 inhibits MESH:D018417 Phenotype e7279db2-c481-11e5-9da3-001a4ae51247 PMC3437860 "Using a mouse model of experimental autoimmune encephalomyelitis (EAE), we show that limited treatment with I-BET-762 or the Myc inhibitor 10058-F4, exclusively during early priming, inhibited the ability of Th1-differentiated 2D2 T cells to induce neuroinflammation in vivo." 1 10058-F4 CHEBI:149696 inhibits GO:0051320 Phenotype a89f6234-bc41-11e5-8abe-001a4ae51246 PMC4216870 These findings suggest that inhibition of MYC in LCC9 cells may restore sensitivity to ICI by both increasing apoptosis and inducing cell cycle arrest.Figure 3Combination of MYC inhibitor and antiestrogen increased G1 cell cycle arrest in endocrine resistant cells.A,Top, ICI (100 nM), 10058-F4 (25 μM), or the combination significantly increased percentage of cells in G1 arrest and reduced percentage of cells in S phase in LCC1 (p< 0.001). 1 10058-F4 CHEBI:149696 inhibits GO:0007049 Phenotype a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 10058-F4 potentiated Imatinib anti-proliferative properties and disrupt the cell cycle distribution. 1 10058-F4 CHEBI:149696 inhibits GO:0007049 Phenotype 5ca21206-bc1d-11e5-8abe-001a4ae51246 PMC2656245 By contrast, pretreatment with either 10058-F4, a c-Myc, inhibitor or PD98059, an ERK1/2 inhibitor, arrested cell proliferation and cell cycle progression when coexistent with TGFβ1 (Figures3,4,5,6). 1 10058-F4 CHEBI:149696 activates GO:0007049 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Because c-Myc gene antagonizes the activity of cell cycle inhibitors as p21 and p27 through different mechanisms, both proteins were analyzed by Western blotting in response to 10058-F4 after 24 hours of treatment (Figure2C-E). 1 10058-F4 CHEBI:149696 inhibits GO:0007049 Phenotype afac0a50-5c1d-11e7-af4d-001a4ae51247 PMC5406870 In HepG2 cells, 10058-F4 arrested the cell cycle (at G0/G1phase), induced cell death and significantly decreased alpha-fetoprotein (AFP) levels, an indicator of the extent of cellular differentiation. 1 10058-F4 CHEBI:149696 activates GO:0006006 Phenotype 58110618-3900-11e8-8636-001a4a160175 26211592 The alternations in glucose metabolism induced by 10058-F4 inhibits cell proliferation and enhances chemosensitivity to GEM Increased glucose and glutamine consumption and enhanced metabolic activity of PDAC have been linked to its aggressiveness[15,16]. 1 10058-F4 CHEBI:149696 activates GO:0009877 Phenotype a69952d6-c96e-11ee-ae05-0050569a1f61 PMC10404563 The MYC inhibitor 10058-F4 also inhibited nodule formation, proliferation, and lipid accumulation in mutant HEPs (Figure 9A and B). 1 10058-F4 CHEBI:149696 inhibits MESH:D017382 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 decreases Reactive Oxygen Species (ROS) and ATP generation Reactive Oxygen Species (ROS) are required for ovarian cancer cell growth [17]. 1 10058-F4 CHEBI:149696 activates MESH:D000077157 Phenotype 6e987f55-f58a-11eb-949b-001a4a160176 30503555 Interestingly, we observed that 2-DG, BPTES or 10058-F4 could only synergize with Sorafenib or Regorafenib to repress PDX#6 tumor growth, but not in the PDX#9 group. 1 10058-F4 CHEBI:149696 inhibits GO:0001906 Phenotype bc2226cc-bbf4-11e5-8abe-001a4ae51246 10.1016/j.exphem.2011.05.002 Rather, the combination with 10058-F4 antagonized the cell-killing effects of various agents in our in vitro study. 1 10058-F4 CHEBI:149696 activates MESH:D005355 Phenotype 1c58a530-dbe1-11ea-86b6-001a4a160176 PMC7198651 Fig. 3The c-Myc inhibitor, 10058-F4, attenuated renal fibrosis in UUO-treated kidneys. 1 10058-F4 CHEBI:149696 inhibits MESH:D005355 Phenotype 1c58a530-dbe1-11ea-86b6-001a4a160176 PMC7198651 ns, no significant; WT, wild type; KO, knockout The c-Myc inhibitor, 10058-F4, attenuated fibrosis significantly in UUO-treated kidneys Consistent with previous study, c-Myc was time dependently increased in UUO-treated kidneys after 3 days by western blot and RT-qPCR analyses (Fig.3a, b). 1 10058-F4 CHEBI:149696 activates MESH:D005355 Phenotype 464c729a-ae96-11ec-b4ed-0050569a1f61 PMCPMC8205594 A recent study reported that the use of a c-Myc inhibitor, 10058-F4, significantly attenuated renal fibrosis in vivo, and in vitro experiments confirmed that c-Myc inhibitors and siRNA silencing of c-Myc blocked IL-1β-induced fibroblast proliferation and activation [10]. 1 10058-F4 CHEBI:149696 inhibits MESH:D009361 Phenotype cc7b507a-cbd6-11ee-9aaa-0050569a1f61 10.1016/j.jff.2015.09.030 The invasion ability of A431-III cells was significantly reduced by the treatment with 200 µM 10058-F4 (Fig. 8F) compared to 0.01% vehicle DMSO (Fig. 8E) in A431-III cells. 1 10058-F4 CHEBI:149696 inhibits MESH:D002051 Phenotype 3e39000e-c8e8-11e5-9ad8-001a4ae51247 17942906 "Results MYC mRNA expression levels and cell growth in cells treated with MYC inhibitor.Previous studies in our laboratory showed that compound 10058-F4 reduced MYC mRNA expression levels in a B-lymphoblastoid and two other Burkitt lymphoma cell lines (22)." 1 10058-F4 CHEBI:149696 activates GO:0007050 Phenotype 7fc7814a-c473-11e5-91a7-001a4ae51247 PMC4420226 c-Myc plays a critical role in proliferation and cell cycle, and levels are elevated in those patients with a high diagnostic CIP2A level.9In AML cell lines and primary cells, 10058-F4 has been shown to inhibit growth, induce cell cycle arrest and cause differentiation.12Here, we have demonstrated that c-Myc inhibition by using the small molecule inhibitor 10058-F4 or siRNA leads to a decrease in CIP2A, reactivation of PP2A, a decrease in BCR-ABL1 tyrosine kinase activity (as assessed by pCrKL), and reduces cellular proliferation. 1 10058-F4 CHEBI:149696 activates GO:0007050 Phenotype a89f6234-bc41-11e5-8abe-001a4ae51246 PMC4216870 ICI, 10058-F4, or the combination induced G1-phase cell cycle arrest in the antiestrogen sensitive LCC1 cells (Figure3A). 1 10058-F4 CHEBI:149696 activates GO:0007050 Phenotype d1281fea-c47d-11e5-9cc6-001a4ae51246 PMC2993546 "In vitro, 10058-F4 exhibited high binding affinity to the bHLH-ZIP domain of c-Myc, promoted dissociation of the c-Myc/Max dimer, prevented binding of the heterodimer to DNA targets, induced cell cycle arrest, and caused apoptosis (Yin et al., 2003;Gomez-Curet et al., 2006;Huang et al., 2006;Lin et al., 2007;Sampson et al., 2007;Wang et al., 2007;Follis et al., 2008)." 1 10058-F4 CHEBI:149696 activates GO:0007050 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 induces cell cycle arrest To examine the mechanism responsible for 10058-F4-mediated inhibition of cell growth, Hey and SKOV3 cells were treated with the indicated concentrations (0–50 uM) of 10058-F4 for 48 hours. 1 10058-F4 CHEBI:149696 activates GO:0007050 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 Importantly, several reports have shown that 10058-F4 affects c-MYC expression and induces cell cycle arrest, inhibits cell growth, promotes apoptosis and confers chemo-sensitivity in a c-MYC specific manner in various cancer cell types[28],[33]–[35]. 1 10058-F4 CHEBI:149696 inhibits GO:0030154 Phenotype 13b9de73-f588-11eb-8b00-001a4a160175 30880164 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0030154 Phenotype e10f2437-dc3c-11ea-894e-001a4a160176 PMC6525070 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0030154 Phenotype d658115e-dc3c-11ea-a281-001a4a160175 PMC6529232 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0030154 Phenotype 7c9d5eae-ae96-11ec-89b1-0050569a791b PMCPMC8718798 To further investigate whether the inhibition of c-MYC can reverse the IL-18-induced osteogenic differentiation of hBMSCs, cells were treated with c-MYC antagonists 10058-F4 and sic-MYC to inhibit c-MYC expression. 1 10058-F4 CHEBI:149696 activates GO:0030154 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 We have previously shown that 10058-F4 stimulates NB differentiation, induces expression of the nerve growth factor (NGF) receptor TrkA and hence rendersMYCN-amplified NB cells sensitive to NGF-mediated differentiation[40]. 1 10058-F4 CHEBI:149696 activates MESH:D051379 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 Importantly, 10058-F4 treatment furthermore increased the survival of TH-MYCNtransgenic mice and showed anti-tumor effects in established aggressive NB xenografts[40]. 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype d658115e-dc3c-11ea-a281-001a4a160175 PMC6529232 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype fdd24a2c-bc51-11e5-ac4e-001a4ae51246 10.1016/j.leukres.2012.11.010 The c-Myc inhibitor 10058-F4 increased apoptosis from 12.8% (DMSO control) to 79.4%. 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype 13b9de73-f588-11eb-8b00-001a4a160175 30880164 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 induces apoptosis To verify that 10058-F4 treatment inhibits cell proliferation by inducing apoptosis, we investigated apoptotic cells by applying an Annexin-V and PI double staining assay after a 24 hours treatment. 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype e10f2437-dc3c-11ea-894e-001a4a160176 PMC6525070 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype 58110618-3900-11e8-8636-001a4a160175 26211592 Results c-Myc inhibitor, 10058-F4, inhibits cell proliferation, induces cell apoptosis and enhances chemosensitivity of PDAC cells to GEM To observe the potential inhibition effect of 10058-F4 in PDAC, we first measured the IC50 value of 10058-F4 in PANC-1 and SW1990 cells by CCK8 assay. 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype a377bd3a-7d11-11ee-add2-0050569a791b 10.1007/s11033-023-08832-4 Stimulatory effects of 10058-F4 on Imatinib-induced apoptotic cell death. 1 10058-F4 CHEBI:149696 inhibits GO:0006915 Phenotype cc1da052-bc2a-11e5-9b9d-001a4ae51247 PMC4673192 RESULTS We have earlier shown that the small molecule MYC inhibitor 10058-F4 induces apoptosis in myeloma cell lines and primary cells. 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype c03a1628-5c31-11e7-8c5f-001a4ae51246 PMC5299732 Among them are the structurally unrelated compounds 10074-G5 and 10058-F4 (Fig.1a), which have been tested in vitro and which produce satisfying effects on neuronal differentiation and the induction of apoptosis [36]. 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 40c871c0-c473-11e5-8491-001a4ae51247 19602047 Ourex vivostudies support this proposal by finding that 10058-F4 induced apopotosis with a synergistic interaction with imatinib, and more importantly, it could overcome IL-3-induced resistance to imatinib (Fig. 8A and B). 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 10058-F4 induces apoptosis To verify that 10058-F4 treatment inhibits cell proliferation by inducing apoptosis, we investigated apoptotic cells by applying an Annexin-V and PI double staining assay after a 24 hours treatment. 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype c0eac18a-3510-11e9-8741-001a4a160176 PMC6146296 Compound 10058-F4, an inhibitor of MYC-MAX heterodimerization, induced apoptosis in primary myeloma clones, but not in U266 MM cells [16]. 1 10058-F4 CHEBI:149696 activates GO:0006915 Phenotype d1281fea-c47d-11e5-9cc6-001a4ae51246 PMC2993546 "In vitro, 10058-F4 exhibited high binding affinity to the bHLH-ZIP domain of c-Myc, promoted dissociation of the c-Myc/Max dimer, prevented binding of the heterodimer to DNA targets, induced cell cycle arrest, and caused apoptosis (Yin et al., 2003;Gomez-Curet et al., 2006;Huang et al., 2006;Lin et al., 2007;Sampson et al., 2007;Wang et al., 2007;Follis et al., 2008)." 1 10058-F4 CHEBI:149696 activates GO:0008219 Phenotype f20ffc53-f58c-11eb-954a-001a4a160176 30098518 Previous studies show that knockdown of MYC results in a decreased viability of MM cells [10], whilst inhibition of MYC-MAX heterodimerization, by the small-molecule compound 10058-F4, causes MM cell death [79]. 1 10058-F4 CHEBI:149696 inhibits GO:0008219 Phenotype ec73cb12-c46b-11e5-8491-001a4ae51247 24686171 "In support of a role for c-Myc suppression in ALL cell death following SK2 inhibition, the c-Myc inhibitor 10058-F4 induced cell death in ALL cell lines in a time-dependent manner similar to that observed following SK2 inhibition (Fig. 4C)." 1 10058-F4 CHEBI:149696 activates GO:0008219 Phenotype 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Induction of apoptosis was further investigated by caspase-3 activity assay, which disclosed that the cell death induced by 10058-F4 in both acute leukemia cell lines is primarily due to the induction of a caspase-3-mediated apoptosis (Fig. 5C). 1 10058-F4 CHEBI:149696 inhibits GO:1903409 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Thus 10058-F4 reduced ROS generation and inhibited cellular ATP production, implicating the relevance of ROS presence and ATP reduction in the cytotoxicity of 10058-F4 in ovarian carcinoma cells. 1 10058-F4 CHEBI:149696 inhibits MESH:D015470 Phenotype 13b9de73-f588-11eb-8b00-001a4a160175 30880164 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits MESH:D015470 Phenotype d658115e-dc3c-11ea-a281-001a4a160175 PMC6529232 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits MESH:D015470 Phenotype e10f2437-dc3c-11ea-894e-001a4a160176 PMC6525070 " Liu A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia Exp." 1 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype edbf1980-c7ab-11ee-ae05-0050569a1f61 10.1016/j.bbrc.2023.05.100 10058-F4, a specificc-Myc inhibitor, can dramatically inhibit the cell growth of cell lines. 1 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype 23ca9158-bc34-11e5-8d2d-001a4ae51247 PMC4032254 Effect of small-molecules on growth inhibition and apoptosis in MYCN-amplified cells The small molecules 10058-F4, 10074-G5, as well as #474 inhibit cell proliferation and induce apoptosis in a variety of c-MYC expressing cells[28],[33],[34],[39], and we have shown that 10058-F4 induces apoptosis and inhibits cell growth in MYCN overexpressing NB cells[40]. 1 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype b60bd7e0-bc41-11e5-ac4e-001a4ae51246 PMC2913983 Compound 10058-F4 treatment decreased the growth of ALL-SIL cells to similar levels regardless of TLX1 expression (Figure4A), suggesting that augmentation of MYC function is a central mechanism of TLX1 contribution to ALL-SIL cell growth. 1 10058-F4 CHEBI:149696 inhibits GO:0016049 Phenotype d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 It was next investigated whether 10058-F4 could increase cell growth inhibition induced by VPA in Jurkat and CCRF-CEM cells, by MTT assay. 1 10058-F4 CHEBI:149696 inhibits MESH:D009447 Phenotype 43242672-3b4e-11e8-8636-001a4a160175 29466695 10058-F4 also suppressed the growth of neuroblastoma tumors in TH-MYCN-driven transgenic mice andMYCN-amplified neuroblastoma cells grown as xenografts in nude mice [72,73]. 1 10058-F4 CHEBI:149696 inhibits GO:0022900 Phenotype 4712aad2-bc3a-11e5-9b9d-001a4ae51247 PMC4160551 Treatment with 10058-F4 for 24 hours in both ovarian cancer cells resulted in a significant decrease in mitochondria ROS levels (Figure4B), suggesting 10058-F4 may inhibit the mitochondrial electron transport chain through the reduction of the c-Myc and Max interaction (21). 1 10058-F4 CHEBI:149696 activates GO:0006096 Phenotype 6e987f55-f58a-11eb-949b-001a4a160176 30503555 Importantly, we observed that c-Myc inhibitor (10058-F4) also largely abolished the promoting effects of Gankyrin on glycolysis and glutaminolysis (Additional file 3:Fig. S3). 1 10058-F4 CHEBI:149696 inhibits GO:0006096 Phenotype 58110618-3900-11e8-8636-001a4a160175 26211592 Mechanistically, this effect may be due, in part, to the decreased glycolysis induced by 10058-F4. 1 10058-F4 CHEBI:149696 inhibits GO:0006096 Phenotype 482d3320-c8b5-11ee-b346-0050569a791b 10.1016/j.intimp.2023.109985 In the present study, we observed that 10058-F4, a c-myc inhibitor could effectively inhibit the glycolysis activity and fibroblast activation in response to TGF-β1. 1 10058-F4 CHEBI:149696 inhibits GO:0072537 Phenotype 482d3320-c8b5-11ee-b346-0050569a791b 10.1016/j.intimp.2023.109985 In the present study, we observed that 10058-F4, a c-myc inhibitor could effectively inhibit the glycolysis activity and fibroblast activation in response to TGF-β1. 1 10058-F4 CHEBI:149696 activates MESH:D054218 Phenotype d3232e98-bc08-11e5-8abe-001a4ae51246 PMC4114592 10058-F4 increases the growth inhibition of Jurkat and CCRF-CEM cells induced by VPA c-Myc is an important oncogene, which contributes to the growth of T-ALL cells, particularly T-ALL cells with Notch1 mutations (5). 1 10058-F4 CHEBI:149696 decreases FPLX:PRC2:complex ProteinFamily 8b1ecbe6-8d8c-11e7-a9fb-001a4ae51247 PMC5485424 Similar to thein vitrofindings,in vivodata showed that 10058-F4 dramatically decreased the levels of PRC2 components and H3K27me3 inTPO-Cre/LSL-BrafV600Emice (Figure5C). 1 10058-F4 CHEBI:149696 inhibits FPLX:Cyclin ProteinFamily 8df9fd94-bbe3-11e5-8abe-001a4ae51246 PMC3782751 We found 10058-F4 reduced Shh-mediated induction of Hk2, Cip2A and Cyclin D2 in a dose-dependent manner (Figure4C). 1 FPLX:PI3K inhibits 10058-F4 CHEBI:149696 ProteinFamily 77dbc1aa-f586-11eb-8a76-001a4a160175 30639430 Notably, the results of time- and concentration-dependent experiments showed that the suppression of PI3K using BKM120 enhanced the cytotoxic effect of 10058-F4 and produced a synergistic effect in Nalm-6 cells (Fig. 2A and B). 1 FPLX:TGFB inhibits 10058-F4 CHEBI:149696 ProteinFamily 5ca21206-bc1d-11e5-8abe-001a4ae51246 PMC2656245 We determined the mitogenic effect of TGFβ1 on cultured rat nucleus pulposus cells and whether the small-molecule c-Myc inhibitor, 10058-F4, obstructed cell proliferation caused by exogenous TGFβ1. 1 FPLX:TGFB inhibits 10058-F4 CHEBI:149696 ProteinFamily e53a2cae-bc2a-11e5-9b9d-001a4ae51247 PMC4546494 Furthermore the TGFβ−Ι induced proliferation response in FUMMT-1 was c-Myc dependent and could be attenuated by using a pharmacological (10058-F4) [29] (Fig.5A) or genetic inhibitor (siRNA) of c-Myc (Fig.5B). 1 FPLX:Caspase inhibits 10058-F4 CHEBI:149696 ProteinFamily c4c8113e-ab80-11e6-9ac8-001a4ae51246 PMC4815801 Therefore, we investigated whether the activation of caspases could be diminished by inhibition of c-Myc using 10058-F4, a selective Myc-Max inhibitor (Huanget al, 2006). 1 MESH:D011374 increases 10058-F4 CHEBI:149696 Phenotype 9999f1d6-c485-11e5-9cc6-001a4ae51246 PMC3346129 RRM2 stimulation by progesterone was significantly abrogated by either UCN-01 or 10058-F4 treatment.Rrm2mRNA level stimulated by progesterone was further inhibited by the treatment with both UCN-01 and 10058-F4. 1 UNIPROT:P01106 activates 10058-F4 CHEBI:149696 Protein eb5e5d5a-abd7-11eb-8ca4-001a4a160176 PMCPMC8036678 Direct c-MYC inhibitors include siRNA DCR-MYC, an MYC-directed LNP-formulated siRNA, the MYC-MAX dimerization inhibitors 10058-F4, 10074-G5, as well as the translation inhibitors CMLD010509/rocaglate and TGR-1202 [128,129,130,131,132]. 1 UNIPROT:P01106 inhibits 10058-F4 CHEBI:149696 Protein 7c20fc82-3800-11e6-b56c-001a4ae51246 PMC4398615 c-MYC was inhibited in MOLM14 and MO7e-BCR/ABL1 using chemical inhibition (10058-F4) or siRNA technology, followed by the above end-joining assays. 1 UNIPROT:P01106 inhibits 10058-F4 CHEBI:149696 Protein 54c1cabe-c8e8-11ee-8b99-0050569a1f61 10.1016/j.bcp.2023.115446 5A and D, c-Myc knockdown or addition of 10058-F4 (20 μM, 48 h) robustly declined the protein levels of GLS1 and SLC1A5, as well as reduced the consumption of glutamine and the levels of glutamate and glutathione in both H446 shNC and H1688 OE cells (Fig. 5E-J).