count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 6 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 BMS-754807 synergizes with 2-DG to promote apoptosis in EKVX cells As 2-DG‒induced IGF1R activation may promote cell survival through various downstream signaling pathways including AKT, we next tested whether BMS-754807 can be used to potentiate the effect of 2-DG in NSCLC cells.|||Therefore, the restoration of LKB1 kinase activity is sufficient to rescue LKB1-inactivated cells from apoptosis induced by the combination of 2-DG and BMS-754807 in EKVX and Lkb1-null MEF cells.|||We next determined whether the restoration of LKB1/AMPK signaling is capable of protecting cells against apoptosis induced by the combination of 2-DG and BMS-754807.|||In genetically defined Lkb1-null MEF cells and EKVX cells, the combination of subtoxic dose of 2-DG and BMS-754807 induced apoptosis.|||BMS-754807 promotes apoptosis. 4 BMS-754807 CHEBI:88339 inhibits GO:0046959 Phenotype 757d680c-ee09-11e5-872c-001a4ae51246 PMC4368495 Finally, exposure to BMS-754807, a pharmacological inhibitor of IGF1R (Carboni et al., 2009; Kamei et al., 2011) for 30 min prior to and during habituation testing, also significantly reduced startle habituation in a dose-dependent manner in wild-type zebrafish at both 5 and 12 dpf (Figures 6C and 6D). 4 BMS-754807 CHEBI:88339 activates CHEBI:175901 Chemical e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "BMS-754807 increases animal survival and further enhances gemcitabine survival benefits In AsPC-1 PDAC murine xenograft study, the median survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice was 21 days in the control group.|||BMS-754807 inhibits the growth of PDAC xenografts and enhances gemcitabine antitumor response BMS-754807 significantly inhibited the growth of AsPC-1 xenografts.|||BMS-754807 inhibits intratumoral proliferation, induces apoptosis and enhances gemcitabine response Further investigation of mechanisms of the antitumor activity of BMS-754807 by immunohistochemical analyses of tumor tissues revealed that the tumors of BMS-754807–treated mice presented a decreased tumor cell proliferation rate." 4 BMS-754807 CHEBI:88339 inhibits MESH:D002470 Phenotype 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 All values are relative to the DMSO control and are presented as mean ± SEM (n = 3) BMS-754807 synergizes with platinum chemotherapeutics to reduce A549 Cell viability To determine if the addition of BMS-754807 could enhance the anticancer effects of platinum based chemotherapeutics at low concentrations, BMS-754807 was combined simultaneously with either cisplatin or carboplatin and the effects on cell viability were compared to those of each single agent.|||BMS-754807 administration was sufficient to reduce cell viability in both A549 and NCI-H358 cells (Fig.2a).|||Fig. 2Treatment with BMS-754807 reduces cell viability in a concentration dependent manner. 4 BMS-754807 CHEBI:88339 activates UNIPROT:P42574 Protein dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Here, we found that BMS-754807 alone slightly induced caspase-3 or PARP cleavage, and this was significantly enhanced by the combination of 2-DG and BMS-754807 in EKVX cells (Fig. 2C).|||We also generated isogenic MEF cell lines with vector, WT, or K78M-mutant LKB1 expression, and the combination of 2-DG and BMS-754807 promoted caspase-3 and PARP cleavage in the vector-treated control cells (Fig. 3C).|||In these MEF isogenic cells, re-establishment of LKB1/AMPK signaling was also capable of suppressing caspase-3 and PARP cleavage induced by the combination of 2-DG and BMS-754807 (Fig. 3C).|||μM of BMS-754807 alone was sufficient to induce caspase-3 and PARP cleavage in H460 cells, but the inclusion of a sub-toxic level of 2-DG (1  4 BMS-754807 CHEBI:88339 activates UNIPROT:P09874 Protein dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 We also generated isogenic MEF cell lines with vector, WT, or K78M-mutant LKB1 expression, and the combination of 2-DG and BMS-754807 promoted caspase-3 and PARP cleavage in the vector-treated control cells (Fig. 3C).|||Here, we found that BMS-754807 alone slightly induced caspase-3 or PARP cleavage, and this was significantly enhanced by the combination of 2-DG and BMS-754807 in EKVX cells (Fig. 2C).|||μM of BMS-754807 alone was sufficient to induce caspase-3 and PARP cleavage in H460 cells, but the inclusion of a sub-toxic level of 2-DG (1 |||In these MEF isogenic cells, re-establishment of LKB1/AMPK signaling was also capable of suppressing caspase-3 and PARP cleavage induced by the combination of 2-DG and BMS-754807 (Fig. 3C). 4 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "Interestingly, BMS-754807 inhibited the proliferation of all PDAC cells tested; importantly, in all lines there were additive inhibitory effects in combination with gemcitabine.|||BMS-754807 inhibits intratumoral proliferation, induces apoptosis and enhances gemcitabine response Further investigation of mechanisms of the antitumor activity of BMS-754807 by immunohistochemical analyses of tumor tissues revealed that the tumors of BMS-754807–treated mice presented a decreased tumor cell proliferation rate.|||Results BMS-754807 inhibits PDAC cell proliferation Analysis of human PDAC cells AsPC-1, BxPC-3, MIA PaCa-2, and Panc-1, revealed that all 4 lines expressed IGF-1R and phospho-IGF-1R.|||BMS-754807 dose-dependently inhibited PDAC cell proliferation, with an inhibition in cell proliferation at 10 μmol/L of 54%, 37%, 49%, and 39% in AsPC-1, BxPC-3, MIA PaCa-2, and Panc-1 cells, respectively." 4 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 Treatment with BMS-754807 inhibits proliferation and induces apoptosis Concentration–response curves were generated to determine the sensitivity of each lung cancer cell line to BMS-754807.|||BMS-754807 also significantly reduced proliferation in A549 but not NCI-H358 cells.|||BMS-754807 significantly inhibitied proliferation in A549 cells (Fig.2d) but not NCI-H358 cells (Fig.2e).|||BMS-754807 significantly increase apoptosis in both A549 and NCI-H358 cells and significantly reduced proliferation in A549 cells. 3 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P12931 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Treatment with BMS-754807 alone inhibited Src phosphorylation on both Tyr416 and Tyr527 residues in A549 cells, but not affected Src phosphorylation levels in NCI-H3255 cells (Figs.|||The combination of dasatinib with BMS-754807 completely blocked the phosphorylation of Src, IR and IGF-1R, and the inhibition was especially prominent in NCI-H3255 cells even at 0.01 µM (Figs. 3 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 We examined whether dasatinib in combination with BMS-754807 inhibited the lung cancer cell proliferation by blocking this pathway.|||Overall, our results suggest that dasatinib in combination with BMS-754807 inhibits the lung cancer cell proliferation in vitro and tumor growth in vitro, which indicates promising evidence for the application of the drug combination in lung cancer therapy. 3 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 BMS-754807 blocks growth, induces apoptosis, and sensitizes MC1 tumorgrafts to docetaxel-induced mitotic catastrophe Several reports have shown that chemotherapy agents such as docetaxel affect the stability of the microtubules and in doing so induce mitotic catastrophe (47, 48).|||Chemotherapy resulted in a 6.7-fold induction of apoptosis compared with vehicle (adjustedP= 0.1), which again was not significant, whereas the combination of BMS-754807 and chemotherapy caused a striking 12-fold induction of apoptosis compared with vehicle-treated tumors (Fig. 6F; Supplementary Fig S4D), which was highly significant (adjustedP= 0.005).|||BMS-754807 caused a 4-fold elevation in apoptosis as measured by cleaved caspase 3 (CC3) from 3% apoptotic cells in vehicle-treated tumors to 11% in BMS-754807–treated tumors (Fig. 6F; Supplementary Fig S4D); however, this elevation was not significant (adjustedP= 0.36). 3 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "BMS-754807 inhibits intratumoral proliferation, induces apoptosis and enhances gemcitabine response Further investigation of mechanisms of the antitumor activity of BMS-754807 by immunohistochemical analyses of tumor tissues revealed that the tumors of BMS-754807–treated mice presented a decreased tumor cell proliferation rate.|||Evaluation of target proteins in tumor tissue lysates showed that BMS-754807 treatment decreased levels of the activated form of IGF-1R and AKT, and induced levels of apoptosis-related proteins, indicating that the BMS-754807 therapy is indeed managing to affect these targets within the local tumor model.|||BMS-754807 blocks IGF signaling proteins and induces apoptosis The effect of BMS-754807 on the IGF/receptor axis was investigated using AsPC-1 and Panc-1 PDAC cell lines that were most responsive to this drug in terms of causing a shift in the gemcitabine IC50." 3 BMS-754807 CHEBI:88339 activates GO:0006914 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 induces autophagy in lung cancer cells.|||Dasatinib in combination with BMS-754807 induced autophagy in lung cancer cells, evidenced by the upregulation of LC3B II and beclin-1, the downregulation of LC3B I and SQSTM1/p62, and the autophagic flux observed with a confocal fluorescence microscopy.|||Therefore, these results indicated that dasatinib in combination with BMS-754807 induced autophagy in lung cancer cells, evidenced by the upregulation of LC3B II and beclin-1, the downregulation of LC3B I and SQSTM1/p62, and the yellow or red fluorescence observed with a confocal fluorescence microscopy. 2 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein 80613e1a-c479-11e5-8491-001a4ae51247 PMC3243810 Another possible explanation for improved targeting with BMS-754807 is that this compound inhibits insulin receptor (IR) signaling as well (27). 2 BMS-754807 CHEBI:88339 activates UNIPROT:P08069 Protein 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "BMS-754807, a pyrrolotriazine and reversible ATP-competitive antagonist of IGF-1R, inhibits the catalytic domain of the IGF-1R (19), and has been shown to block the activity of both IGF-1R and IR inin vitrokinase assays." 2 BMS-754807 CHEBI:88339 activates UNIPROT:P08069 Protein 2c743536-c47f-11e5-85e4-001a4ae51246 20807811 BMS-754807 may cause transcriptional regulation of IGF-IR, whereas MAB391 induces IGF-IR internalization/degradation (15), leading to a subsequent decrease in IGF-IR cell surface expression in Rh41-MAB391R cells. 2 BMS-754807 CHEBI:88339 activates UNIPROT:O60674 Protein 64d803a4-c9ca-11ee-8b99-0050569a1f61 PMC9837451 NT157 causes IRS2 degradation, whereas BMS-754807 inhibits IGF1R kinase activity.35Both inhibitors, in a dose-dependent manner, effectively inhibited murine sCFU-E growth (Figure 7C) and the ability of JAK2(V617F)-positive PV mononuclear cells to form erythroid colonies under low Epo conditions (Figure 7D). 2 BMS-754807 CHEBI:88339 decreases UNIPROT:P06400 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. 2 BMS-754807 CHEBI:88339 inhibits GO:0010467 Phenotype efca4eb8-00ab-11f0-9c09-0050569a791b 10.1016/j.prp.2024.155620 Treatment with the different anti- BMS-754807 reversed the gene expression signature in test models and showed sensitivity to the inhibitor in TNBC cells. 2 BMS-754807 CHEBI:88339 activates GO:0008283 Phenotype e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 BMS-754807 addition decreases gemcitabine IC Gemcitabine, a standard anti-PDAC chemotherapy agent, inhibited cell proliferation of PDAC lines in a dose-dependent manner. 2 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "BMS-754807 was found to inhibit tumor growth in a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with TGI ranging from 53% to 115%." 2 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype efca4eb8-00ab-11f0-9c09-0050569a791b 10.1016/j.prp.2024.155620 BMS-754807 co-treated with docetaxel showed tumor growth inhibition and regression inin vivoexperimental model, which was associated with reduced proliferation, and increased apoptosis. 2 BMS-754807 CHEBI:88339 inhibits GO:0016049 Phenotype a5af49fe-ae93-11ec-8f68-0050569a1f61 PMC8732810 Over time, cell growth was reduced by 0.5 μM BMS-754807 in SNU-1, MKN74 and AGS and by 5 μM BMS-754807 in all cells (two-way ANOVA; p < 0.0002). 2 BMS-754807 CHEBI:88339 activates MESH:D054218 Phenotype 7964fd04-f597-11eb-9801-001a4a160176 31042587 For example, the IGF1R inhibitors BMS-536924 and BMS-754807 decreased cell growth and reduced the survival of human T-ALL cell lines and primary T-ALL cells [12], similarly to PI3K/AKT/mTOR inhibitors [13,14]. 2 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:ERK ProteinFamily 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 A possible explanation for BMS-754807 to block ERK phosphorylation in AsPC-1 tumor lysates but not in AsPC-1 or Panc-1 cell lines is the significant activity of stromal cells within tumors, in which ERK-phosphorylation has been shown to be blocked by BMS-754807 (own data, not shown here). 2 BMS-754807 CHEBI:88339 decreases UNIPROT:Q13309 Protein 7310a5e2-f57a-11eb-85e3-001a4a160175 PMC7855212 Together, these data suggest that combination treatment with BMS-754807 and metformin leads to diminished levels of Skp2, therefore allowing p27 to accumulate and suppress cell cycle progression in TNBC cells.Fig.|||We found that BMS-754807 treatment led to a reduced level of Skp2, and that the combination treatment caused a further reduction of Skp2 (Fig.4b). 2 BMS-754807 CHEBI:88339 inhibits UNIPROT:Q13309 Protein 7310a5e2-f57a-11eb-85e3-001a4a160175 PMC7855212 4Combined treatment with metformin and BMS-754807 synergistically enhances p27 and p-p27(T187) but reduces Skp2.|||However, it is yet to be determined how Skp2 is reduced by BMS-754807 and further diminished by combination treatment with metformin and BMS-754807. 2 BMS-754807 CHEBI:88339 activates UNIPROT:P42574 Protein e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "Evaluation of intratumoral apoptosis by analyzing expression of cleaved caspase-3 and cleaved PARP-1 proteins revealed that BMS-754807 and gemcitabine both induced cleavage of caspase-3 and PARP-1, and that the combination of these 2 agents had additive effects on cleavage of these apoptosis-related proteins (Fig. 4C).|||As previously reported in a human rhabdomyosarcoma cell line (21), we observed that in PDAC cells BMS-754807 treatment caused a decrease in phosphorylated IGF-1R and its downstream signaling protein phospho-AKT, and increased cleavage of apoptosis-related caspase-3 and PARP-1 proteins." 2 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P06213 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 The combination of dasatinib with BMS-754807 completely blocked the phosphorylation of Src, IR and IGF-1R, and the inhibition was especially prominent in NCI-H3255 cells even at 0.01 µM (Figs.|||BMS-754807 appeared to partially inhibit IR phosphorylation, but completely blocked IGF-1R phosphorylation even at 0.01 µM. Treatment with dasatinib did not affect IGF-1R phosphorylation in A549 and NCI-H3255 cells. 2 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein b4d827b6-ae93-11ec-840e-0050569a791b PMCPMC8833961 To inhibit IGF1R, cells at day 0 were treated with 20 nM BMS-754807 (BMS, Hycultec, Beutelsbach, Germany) or DMSO and collected for expression analyses at day 3.|||IGF1R Inhibition Has No Impact on miR-100 Levels To determine whether inhibiting IGF1R would affect miR-100 expression in BMSC, an inhibitor of IGF1R, BMS-754807 (BMS), was used. 2 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Fulvestrant was the most effective hormonal therapy at enhancing the inhibition of IGF-1R phosphorylation by BMS-754807.|||Western blot analysis Inhibition of IGF-1R and insulin receptor phosphorylation and ERK/Akt pathways by BMS-754807 alone or combination with 4-OH tamoxifen (10 μmol/L), letrozole (10 μmol/L), or fulvestrant (100 nmol/L) were determined by Western blotting. 2 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Meanwhile, treatment with BMS-754807 alone induced IR expression and suppressed IGF-1R phosphorylation in both A549 and NCI-H3255 cells in a dose-dependent manner (Figs.|||The combination of dasatinib with BMS-754807 completely blocked the phosphorylation of Src, IR and IGF-1R, and the inhibition was especially prominent in NCI-H3255 cells even at 0.01 µM (Figs. 2 BMS-754807 CHEBI:88339 activates UNIPROT:P09874 Protein e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "As previously reported in a human rhabdomyosarcoma cell line (21), we observed that in PDAC cells BMS-754807 treatment caused a decrease in phosphorylated IGF-1R and its downstream signaling protein phospho-AKT, and increased cleavage of apoptosis-related caspase-3 and PARP-1 proteins.|||Evaluation of intratumoral apoptosis by analyzing expression of cleaved caspase-3 and cleaved PARP-1 proteins revealed that BMS-754807 and gemcitabine both induced cleavage of caspase-3 and PARP-1, and that the combination of these 2 agents had additive effects on cleavage of these apoptosis-related proteins (Fig. 4C)." 2 BMS-754807 CHEBI:88339 activates UNIPROT:O95477 Protein 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "Importantly, combination of BMS-754807 with cetuximab at a variety of dose levels produced antitumor activities (TGD, 23–38 days) that were generally greater than either agent alone (TGD, 15–21 days) or single-agent cetuximab (TGD, 14 days;Fig. 6), reaching statistical significance when cetuximab (0.25 mg/mouse) was combined with BMS-754807 at its MTD (25 mg/kg), as well as at a dose level 2-fold below (Table 2;Fig. 6).|||At its MTD (25 mg/kg, orally, twice daily for 17 days), BMS-754807 produced 61% TGI and TGD of 7 days." 2 BMS-754807 CHEBI:88339 activates CHEBI:33364 Chemical 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 To evaluate whether BMS-754807 could enhance the effects of platinum chemotherpeutics, A549 and NCI-H358 cell survival was assessed following simultaneous administration of either BMS-754807 and cisplatin or BMS-754807 and carboplatin.|||All values are relative to the DMSO control and are presented as mean ± SEM (n = 3) BMS-754807 synergizes with platinum chemotherapeutics to reduce A549 Cell viability To determine if the addition of BMS-754807 could enhance the anticancer effects of platinum based chemotherapeutics at low concentrations, BMS-754807 was combined simultaneously with either cisplatin or carboplatin and the effects on cell viability were compared to those of each single agent. 2 BMS-754807 CHEBI:88339 activates MESH:D000077267 Phenotype f81f4c58-351a-11e8-a51f-001a4a160176 28236033 Therefore, although BMS-754807 contributes to the anti-proliferative effect of triplet therapy with trastuzumab and fulvestrant, its effect is sub-additive.|||Hou et al. have reported that BMS-754807 synergizes in vitro and in vivo with tamoxifen, letrozole, or fulvestrant in breast cancer models [65]; in addition, the combination resulted in upregulation of HER2, EGFR, and HER4, supporting our proposal that triple-targeting, and inhibiting the entire HER axis, would be of benefit. 2 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Furthermore, dasatinib (18 mg/kg) in combination with BMS-754807 (18 mg/kg) inhibited the growth of tumors in NCI-H3255 xenografts without changing the bodyweight.|||Dasatinib in combination with BMS-754807 inhibits tumor growth in lung cancer xenograft models. 2 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 84acb41e-c776-11ee-8b99-0050569a1f61 10.1016/j.ejmech.2023.115495 In H460 xenografted mice model, combination of BMS-754807 (6.25 mg/kg, oral administration) and 2-deoxyglucose (6.25 mg/kg, oral administration) suppressed 69.0% tumor growth without great influence on body weight and restored G2/M phase cell cycle arrest, while the tumor growth was not apparently inhibited in monotherapy [39].|||In OE19 esophageal adenocarcinoma cell-derived subcutaneous xenografted mice model, BMS-754807 (25 mg/kg, intraperitoneal injection) exhibited a significant tumor regression response to 62.4% and suppressed 52.0% tumor growth without any significant change in mice body weight. 2 BMS-754807 CHEBI:88339 activates MESH:D004249 Phenotype f18a81de-5801-11e6-8f02-001a4ae51247 PMC5302955 We first observed that BMS-754807 caused a significant increase in DNA damage along with activation of the ATR pathway, as measured by the formation of γ-Histone2AX (γH2AX) and phosphorylation of Chk1 on Serine 345 respectively (Figure2A).|||Higher concentrations of BMS-754807 also induced DNA damage (Figure2B) leading to a four-fold increase in γH2AX levels. 2 BMS-754807 CHEBI:88339 activates MESH:D011123 Phenotype dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Because H460 cells have wild-type p53, BMS-754807 induced polyploidy formation is unlikely to be related to p53 inactivation.|||The inhibition of IGF1R function has previously been shown to enhance radiation-induced polyploidy in DU145 prostate cancer cells [31], and BMS-754807 was able to induce polyploidy with 8n-DNA content in 4% of the cell population [16]. 2 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 Since only BMS-754807 induced apoptosis, we then performed a similar experiment with shIGF-1R PC-3 cells to determine whether decreased IGF-1R expression specifically increased apoptosis.|||Similarly to shRNA-mediated knockdown ofIGF-1R, BMS-754807 affected proliferation and increased apoptosis, whereas shRNA toSRChad less effect on proliferation, as demonstrated previously[11]. 2 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Nab-paclitaxel and BMS-754807 induced the expression of apoptosis-related cleaved caspase-3 protein, while combination treatment generated an additive effect (Figure7).|||Intratumoral apoptosis, measured by TUNEL assay, revealed that the nab-paclitaxel and BMS-754807 monotherapy increased intratumoral apoptosis that was further increased in the combination therapy group. 2 BMS-754807 CHEBI:88339 inhibits MESH:D008024 Phenotype a5af49fe-ae93-11ec-8f68-0050569a1f61 PMC8732810 Ligand-dependent protection of SNU-1 and NUGC3 from anoikis in serum-free medium, and from  apoptosis, was inhibited also by BMS-754807 (data not shown).|||This ligand-dependent protection was prevented by BMS-754807 in serum-free medium (two-way ANOVA; p < 0.001). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P23443 Protein be570ba0-c46f-11e5-91a7-001a4ae51247 PMC4122288 "CDK4/6 knockdown in MIA-PaCa-2 cells lead to increased phospho-S6K1 that was strongly reduced by BMS-754807, which had no effect on control siRNA–transfected cells (Fig. 5B)." 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P23443 Protein be570ba0-c46f-11e5-91a7-001a4ae51247 PMC4122288 "Although concurrent treatment with BMS-754807 and PD-0332991 significantly reduced S6K1 phosphorylation in the sensitive MIA-PaCa-2 and HuP-T3 cell lines (Fig. 4B), it had no effect in PANC-03-27 or CFPAC-1 cells, in which the inhibitors do not synergize." 1 BMS-754807 CHEBI:88339 decreases UNIPROT:P03372 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Indeed, despite having similarin vitroandin vivoefficacy during treatment, letrozole in combination with BMS-754807 decreased ER expression, whereas tamoxifen in combination with BMS-754807 led to increased ER expression by Western blotting (Fig 4). 1 BMS-754807 CHEBI:88339 activates UNIPROT:Q13309 Protein 7310a5e2-f57a-11eb-85e3-001a4a160175 PMC7855212 However, it is yet to be determined how Skp2 is reduced by BMS-754807 and further diminished by combination treatment with metformin and BMS-754807. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P04732 Protein 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "At its MTD (25 mg/kg, orally, twice daily for 17 days), BMS-754807 produced 61% TGI and TGD of 7 days." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:Q9H9S0 Protein e6cb38f2-f58b-11eb-8c53-001a4a160175 30956007 Western blot assays demonstrated that addition of both BMS-754807 and PPP blocked the promotion of NANOG, OCT4, SOX2 protein expression induced by 100 ng/mL IGF2, with no significant difference between the BMS-754807- and PPP-treated groups (Figure 4C–F;P< 0.05). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P04629 Protein 82e632ea-3406-11e8-9fbf-001a4a160176 PMC5610669 inhibition of TrkA, TrkB, and aurora kinases by BMS-754807 [60], which may influence their therapeutic use. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P54764 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 For example, both hormonal agents increasedERBB4expression, which was enhanced by BMS-754807;EPHA4, MET, andTGFBR2expression were only affected by tamoxifen, not by letrozole. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:Q01860 Protein e6cb38f2-f58b-11eb-8c53-001a4a160175 30956007 Western blot assays demonstrated that addition of both BMS-754807 and PPP blocked the promotion of NANOG, OCT4, SOX2 protein expression induced by 100 ng/mL IGF2, with no significant difference between the BMS-754807- and PPP-treated groups (Figure 4C–F;P< 0.05). 1 BMS-754807 CHEBI:88339 activates UNIPROT:P42574 Protein 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Furthermore, BMS-754807 treatment caused a concomitant increase in the apoptosis marker proteins cleaved caspase-3 and cleaved PARP-1 (Figure5). 1 BMS-754807 CHEBI:88339 decreases UNIPROT:P11802 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P01308 Protein 76379c4c-c463-11e5-9cbe-001a4ae51247 PMC4722749 The receptor involved is of clinical importance because drugs such as figitumumab, cixutumumab, ganitumab and dalotuzumab are directed specifically against the type I IGF receptor [16–19] whereas BMS-754807 and linisitinib inhibit both the type I IGF and insulin receptors [20,21]. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P01308 Protein 58c06066-bc4f-11e5-8abe-001a4ae51246 PMC3747439 BMS-754807, is predominantly a dual type I IGF receptor and insulin receptor inhibitor which inhibits MET, TRK A, TRK B, Aurora A, and Aurora B kinases at high concentrations and INSM-18 inhibits type I IGF and insulin receptors and ErbB2 [254,267]. 1 BMS-754807 CHEBI:88339 decreases UNIPROT:Q00534 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P06213 Protein 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "BMS-754807, a pyrrolotriazine and reversible ATP-competitive antagonist of IGF-1R, inhibits the catalytic domain of the IGF-1R (19), and has been shown to block the activity of both IGF-1R and IR inin vitrokinase assays." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 The inhibition of proliferation observed with BMS-754807 was more pronounced in both cell lines than with shIGF-1R, suggesting that the phenotype seen with BMS-754807 is likely due, in part, to the ability of BMS-754807 to inhibit the insulin receptor (IR) as well[26]. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein f27c11f0-3a8d-11e8-9192-001a4a160175 PMC5518922 The only drugs that inhibit InsR, linsitinib (OSI-906) and BMS-754807, exist as dual IGF1R/InsR tyrosine kinase inhibitors. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 BMS-754807 is a specific inhibitor of insulin receptor (IR) and/or IGF-IR [20]. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P06213 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Western blot analysis Inhibition of IGF-1R and insulin receptor phosphorylation and ERK/Akt pathways by BMS-754807 alone or combination with 4-OH tamoxifen (10 μmol/L), letrozole (10 μmol/L), or fulvestrant (100 nmol/L) were determined by Western blotting. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P06213 Protein fe97d132-c464-11e5-85e4-001a4ae51246 PMC3784719 As expected, both BMS-754807 and OSI-906 inhibited the unphosphorylated IR in the screening panel (Fig. 5,CandD). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Since BMS-754807 inhibits both IGF-1R and IR signaling, dysregulation of glucose homeostasis is an important concern, and therefore the advantage of its antitumor effects might have to be balanced with the potential for metabolic side effects. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P06213 Protein 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 In contrast, BMS-754807 completely blocked IGF-IR/InsR phosphorylation. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P06213 Protein ab1815b8-3905-11e8-a51f-001a4a160176 28062706 Upon stimulation with the IGF1R ligand IGF1, phosphorylation of the IGF1R and INSR and the downstream AKT signaling was impaired by BMS-754807 and the combination with PKC412; the same pattern was observed upon serum stimulation (Supplementary Fig. S3B). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein 4327617e-bbfe-11e5-9b9d-001a4ae51247 PMC3356071 In anin vitromodel, BMS-754807 was able to attenuate the hyperactivity of the IR pathway in murine fibroblasts that are null for the IGF-IR (Dinchuk et al.,2010). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P06213 Protein e6778eca-5cbc-11e7-af4d-001a4ae51247 PMC4674309 BMS-754807 is a reversible inhibitor to both IGF-IR and InsR, which is very potent with theKivalue of <2 nmol/L. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 BMS-754807 alone very effectively inhibited pIGF-1R and pAKT and had modest effects on pERK1/2 in MCF-7/AC-1 cellsin vitro. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Since BMS-754807 inhibits both IGF-1R and IR signaling, dysregulation of glucose homeostasis is an important concern, and therefore the advantage of its antitumor effects might have to be balanced with the potential for metabolic side effects. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P08069 Protein d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 BMS-754807 appeared to partially inhibit IR phosphorylation, but completely blocked IGF-1R phosphorylation even at 0.01 µM. Treatment with dasatinib did not affect IGF-1R phosphorylation in A549 and NCI-H3255 cells. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein e6778eca-5cbc-11e7-af4d-001a4ae51247 PMC4674309 BMS-754807 is a reversible inhibitor to both IGF-IR and InsR, which is very potent with theKivalue of <2 nmol/L. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein ab1815b8-3905-11e8-a51f-001a4a160176 28062706 Upon stimulation with the IGF1R ligand IGF1, phosphorylation of the IGF1R and INSR and the downstream AKT signaling was impaired by BMS-754807 and the combination with PKC412; the same pattern was observed upon serum stimulation (Supplementary Fig. S3B). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Results BMS-754807 inhibits 2-DG-induced IGF1R phosphorylation We previously demonstrated that 2-DG treatment activates the pro-survival AKT pathway independently of glycolysis inhibition [1]. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "Evaluation of target proteins in tumor tissue lysates showed that BMS-754807 treatment decreased levels of the activated form of IGF-1R and AKT, and induced levels of apoptosis-related proteins, indicating that the BMS-754807 therapy is indeed managing to affect these targets within the local tumor model." 1 BMS-754807 CHEBI:88339 decreases UNIPROT:P08069 Protein 2c743536-c47f-11e5-85e4-001a4ae51246 20807811 "The mechanism by which BMS-754807 causes the chronic loss of IGF-IR expression is an interesting question, and it could potentially be through transcriptional regulation and protein degradation." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein d61033cc-351d-11e8-8f56-001a4a160175 28515235 BMS-754807 is a specific inhibitor for IGF1R (Bid et al., 2013;Carboni et al., 2009), while NVP-AEW541 is a more general inhibitor of the insulin and IGF pathways as it inhibits the kinase activity of those receptors (García-Echeverría et al., 2004). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein 06f677d2-8d7e-11e7-a59b-001a4ae51247 PMC5641874 BMS-754807 suppressed phosphorylation of the IGF-1R in all three of these cell lines (supplemental Fig. 3A). 1 BMS-754807 CHEBI:88339 activates UNIPROT:P08069 Protein 298aa5d0-c47a-11e5-85e4-001a4ae51246 21266413 Pharmacological inhibition of IGF signaling NVP-AEW541 and BMS-754807, LY294002 and U0126 were used to inhibit the Igf1r, PI3K and Mek1/2 activities, respectively. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P08069 Protein e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "As previously reported in a human rhabdomyosarcoma cell line (21), we observed that in PDAC cells BMS-754807 treatment caused a decrease in phosphorylated IGF-1R and its downstream signaling protein phospho-AKT, and increased cleavage of apoptosis-related caspase-3 and PARP-1 proteins." 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P08069 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Fulvestrant was the most effective hormonal therapy at enhancing the inhibition of IGF-1R phosphorylation by BMS-754807. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P08069 Protein f18a81de-5801-11e6-8f02-001a4ae51247 PMC5302955 BMS-754807 was found to inhibit phosphorylation of the IGF-1R, and activation of the PI3-K and MAPK pathways in response to IGF-1 (Supplementary Figure S1). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P08069 Protein 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 In contrast, BMS-754807 completely blocked IGF-IR/InsR phosphorylation. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P08069 Protein f2224eec-3526-11e9-9cf0-001a4a160175 PMC5984514 IGF1 was effective through the IGF1 receptor (IGF1R) as IGF1R antagonist BMS-754807 (Fig. 2B) and siRNA-mediated knockdown of theIgf1rgene (Fig. 2CandD) significantly attenuated IGF1-induced inhibition ofFgf23gene expression. 1 BMS-754807 CHEBI:88339 decreases UNIPROT:O00625 Protein 2a527648-d47c-11e5-9963-001a4ae51246 25527633 "SK-CO-1 cells withIRS2CNG had higher expression levels of IRS2 protein; pIGF-1R–pIR and pAKT levels increased in response to individual ligand stimulation, and were inhibited by BMS-754807 treatment in a dose-dependent manner (Fig. 5A)." 1 BMS-754807 CHEBI:88339 increases UNIPROT:P46527 Protein 7310a5e2-f57a-11eb-85e3-001a4a160175 PMC7855212 As shown in Fig.4, metformin alone did not appear to have a significant impact on p27 and p-p27(T187) expression levels, BMS-754807 alone led to an increase in both total and phosphorylated levels of p27, and the drug combination caused a further increase of the total and phosphorylated levels of p27, consistent with the findings from RPPA (Fig.3b). 1 BMS-754807 CHEBI:88339 decreases UNIPROT:P21589 Protein 1c30a7f0-72d7-11e8-8367-001a4a160176 PMC6093223 BMS-754807 dramatically reduced EN protein levels (Fig. 3c,left panel) and blocked EN-induced tumor cell proliferation as assessed by BrdU staining of tumor sections (Fig. 3d). 1 BMS-754807 CHEBI:88339 activates UNIPROT:P05019 Protein 298aa5d0-c47a-11e5-85e4-001a4ae51246 21266413 Pharmacological blockade of IGF signaling by NVP-AEW541 and BMS-754807, two structurally distinct Igf1r inhibitors, attenuated re-oxygenation-induced catch-up growth. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P05019 Protein 76379c4c-c463-11e5-9cbe-001a4ae51247 PMC4722749 The receptor involved is of clinical importance because drugs such as figitumumab, cixutumumab, ganitumab and dalotuzumab are directed specifically against the type I IGF receptor [16–19] whereas BMS-754807 and linisitinib inhibit both the type I IGF and insulin receptors [20,21]. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P05019 Protein 72cfadfc-f595-11eb-8f8c-001a4a160175 PMC7062569 001 We then assessed whether BMS-536924 and/or BMS-754807 could block Mn2+-induced IGF signaling in these cells, to validate that IR/IGFR signaling was required for the effects on p-IGFR, p-AKT, and/or p-S6 effects. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P05019 Protein 58c06066-bc4f-11e5-8abe-001a4ae51246 PMC3747439 BMS-754807, is predominantly a dual type I IGF receptor and insulin receptor inhibitor which inhibits MET, TRK A, TRK B, Aurora A, and Aurora B kinases at high concentrations and INSM-18 inhibits type I IGF and insulin receptors and ErbB2 [254,267]. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P05019 Protein a5af49fe-ae93-11ec-8f68-0050569a1f61 PMC8732810 Effective inhibition of ligand-stimulated phosphorylation of IGF receptors and Akt by BMS-754807 in serum-free medium was confirmed in SNU-1 and NUGC3 (Fig. 2e). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P05019 Protein e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "BMS-754807 blocks IGF signaling proteins and induces apoptosis The effect of BMS-754807 on the IGF/receptor axis was investigated using AsPC-1 and Panc-1 PDAC cell lines that were most responsive to this drug in terms of causing a shift in the gemcitabine IC50." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P35913 Protein 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "BMS-754807 was found to inhibit tumor growth in a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with TGI ranging from 53% to 115%." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:Q04656 Protein 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 BMS-754807 inhibits growth of MC1 TNBC tumorgrafts and, when combined with chemotherapy, causes complete regression Our studies identified TNBC and TNBC cell lines as having an active IGF pathway. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P09874 Protein a5af49fe-ae93-11ec-8f68-0050569a1f61 PMC8732810 PARP cleavage indicative of programmed cell death was induced by 0.5 and 5.0 µM BMS-754807 (Fig. 2d). 1 BMS-754807 CHEBI:88339 activates UNIPROT:P09874 Protein 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Furthermore, BMS-754807 treatment caused a concomitant increase in the apoptosis marker proteins cleaved caspase-3 and cleaved PARP-1 (Figure5). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein UNIPROT:P31749 Protein ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 In contrast, BMS-754807 partially, but not completely, reduced both phosphorylation of both Akt1 and 2 in the presence of IGF-1. 1 BMS-754807 CHEBI:88339 decreases UNIPROT:P31749 Protein 2a527648-d47c-11e5-9963-001a4ae51246 25527633 "SK-CO-1 cells withIRS2CNG had higher expression levels of IRS2 protein; pIGF-1R–pIR and pAKT levels increased in response to individual ligand stimulation, and were inhibited by BMS-754807 treatment in a dose-dependent manner (Fig. 5A)." 1 BMS-754807 CHEBI:88339 phosphorylatesProtein UNIPROT:P31749 Protein ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 Dual blockade of IGF-1R and SFK with combined BMS-754807 and dasatinib completely inhibits detectable Akt1 and 2 phosphorylation in the presence of IGF-1 (Fig. 2B, C). 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:P31749 Protein 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 BMS-754807 alone very effectively inhibited pIGF-1R and pAKT and had modest effects on pERK1/2 in MCF-7/AC-1 cellsin vitro. 1 BMS-754807 CHEBI:88339 activates UNIPROT:P04626 Protein 58c06066-bc4f-11e5-8abe-001a4ae51246 PMC3747439 BMS-754807, is predominantly a dual type I IGF receptor and insulin receptor inhibitor which inhibits MET, TRK A, TRK B, Aurora A, and Aurora B kinases at high concentrations and INSM-18 inhibits type I IGF and insulin receptors and ErbB2 [254,267]. 1 BMS-754807 CHEBI:88339 increases UNIPROT:Q9UNQ0 Protein 10029685-f53c-11eb-acdc-001a4a160175 29253837 On the other hand, BMS-754807 was not addressed to induce BCRP expression alluding to the potential development of different resistance mechanisms[194]. 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:Q9H0P0 Protein be570ba0-c46f-11e5-91a7-001a4ae51247 PMC4122288 "BMS-754807 (15–500 nmol/L) and PD-0332991 (0.15–5.0 μmol/L) synergized significantly to reduce viability up to 70% to 80% in the cell lines MIA-PaCa-2, PSN1, HuP-T3, and YAPC and showed synergy limited to a part of the effect range in the HPAC and AsPC-1 lines (Fig. 1E)." 1 BMS-754807 CHEBI:88339 inhibits UNIPROT:O14965 Protein 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 However, further intrigue is provided by the finding that BMS-754807 actually inhibits AURKA (31), albeit with lower affinity than IGF-IR. 1 BMS-754807 CHEBI:88339 activates CHEBI:49375 Chemical 57e75fe6-c46f-11e5-9cc6-001a4ae51246 PMC4326029 "Notably, these results are correlated with the drug synergy analysis that showed that crizotinib (MET TKI) and BMS-754807 (IGF1R TKI) were strongly synergistic with dasatinib in H2286 and HCC366, respectively (Fig. 4B and C)." 1 BMS-754807 CHEBI:88339 inhibits CHEBI:29108 Chemical e6cb38f2-f58b-11eb-8c53-001a4a160175 30956007 However, only the addition of BMS-754807 inhibited the calcium deposition induced by IGF2, whereas the addition of PPP had no impact on calcium deposition in comparison with the addition of IGF2 (Figure 6A). 1 BMS-754807 CHEBI:88339 activates MESH:D013629 Phenotype f81f4c58-351a-11e8-a51f-001a4a160176 28236033 Hou et al. have reported that BMS-754807 synergizes in vitro and in vivo with tamoxifen, letrozole, or fulvestrant in breast cancer models [65]; in addition, the combination resulted in upregulation of HER2, EGFR, and HER4, supporting our proposal that triple-targeting, and inhibiting the entire HER axis, would be of benefit. 1 BMS-754807 CHEBI:88339 activates MESH:D016190 Phenotype 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 At all concentrations of cisplatin and carboplatin used, the addition of BMS-754807 enhanced the effects of cisplatin and carboplatin (Fig.5a, b). 1 BMS-754807 CHEBI:88339 activates GO:0010467 Phenotype f18a81de-5801-11e6-8f02-001a4ae51247 PMC5302955 The results indicated that although BMS-754807 inhibits both IGF-IR and IR, many of the gene expression changes caused by BMS-754807 were due to IGF-IR inhibition alone. 1 BMS-754807 CHEBI:88339 inhibits MESH:D002289 Phenotype dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Furthermore, we demonstrated that the combination of 2-DG and BMS-754807 inhibits the proliferation of non-small cell lung cancer bothin vitroandin vivo. 1 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Furthermore, we demonstrated that the combination of 2-DG and BMS-754807 inhibits the proliferation of non-small cell lung cancer bothin vitroandin vivo. 1 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype e8b349fc-6fbd-11ee-add2-0050569a791b 10.1007/s40495-023-00336-w In terms of other combinatorial treatments with metformin, an in vitro study showed that the combination of metformin and BMS-754807 (a potent IGF-1R and IR antagonist) synergistically inhibited cell proliferation in a panel of TNBC cell lines more effectively than either drug alone, which was associated with stabilization of the levels of the CDK-inhibitor p27/Kip1 [73•]. 1 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype caa36b60-5d89-11e7-8e96-001a4ae51246 PMC5435685 BMS-754807 treatment abolished low [Ca2+]-induced NaR cell proliferation inTg(igfbp5a:GFP) larvae (Fig.6a). 1 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Both, nab-paclitaxel and BMS-754807, inhibited PDAC cells proliferation. 1 BMS-754807 CHEBI:88339 activates GO:0008283 Phenotype ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 Similarly to shRNA-mediated knockdown ofIGF-1R, BMS-754807 affected proliferation and increased apoptosis, whereas shRNA toSRChad less effect on proliferation, as demonstrated previously[11]. 1 BMS-754807 CHEBI:88339 inhibits GO:0008283 Phenotype 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "The cellular IC50values for inhibition of proliferation by BMS-754807 in IGF-1R-Sal and Rh41 were in the low nmol/L range (7 and 5 nmol/L, respectively), compared with the weak activity observed in Geo cells (365 nmol/L) tested in media containing 10% FBS (which includes a variety of growth factors; Supplementary Table S4)." 1 BMS-754807 CHEBI:88339 activates MESH:D009369 Phenotype 76ed8cc2-bc35-11e5-ac4e-001a4ae51246 PMC4427104 However, in epithelial OC, the IGF-1R inhibitor BMS-754807 inhibits mesenchymal, epithelial, and hematopoietic tumor growth, and has activity in a xenograft model of epithelial OC [17,18]. 1 BMS-754807 CHEBI:88339 activates MESH:D009369 Phenotype 1ec62d29-f58b-11eb-94cc-001a4a160176 30771873 In EOC, the IGF-1R inhibitor BMS-754807 inhibits mesenchymal, epithelial, and hematopoietic tumor growth, with reported activity in a xenograft model (Weroha and Haluska, 2008). 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "We observed that in a PDAC murine xenograft model, BMS-754807 inhibited local tumor growth as single agent and more importantly, caused additive effects in combination with gemcitabine." 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 In these models, BMS-754807 inhibited tumor growth as a single agent and more importantly, caused additive effects in combination with nab-paclitaxel. 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 1c5859d6-bbd1-11e5-80fb-001a4ae51246 PMC3605519 BMS-754807 effectively inhibited the growth of a broad range of human tumor typesin vitroand was active in multiple xenograft tumor models (Carboni et al., 2009). 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 44e43b18-ae96-11ec-8b2e-0050569a1f61 PMCPMC8490822 On the other hand BMS-754807 monotherapy significantly decreased net tumor growth to 149.79 ± 35.8 mm , whereas after flavopiridol + BMS-754807 combination therapy it was further decreased significantly to 24.27 ± 18.27 mm (Figure 4C). 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 Whereas, as expected, treatment with dasatinib alone exhibited some inhibition of bone destruction, the combination of dasatinib and BMS-754807 more effectively inhibited intratibial tumor growth in the bone (Fig. 4A, B). 1 BMS-754807 CHEBI:88339 inhibits MESH:D009369 Phenotype 10029685-f53c-11eb-acdc-001a4a160175 29253837 Moreover, addition of docetaxel in BMS-754807 treated TNBC xenografts eliminated tumor growth[149]. 1 BMS-754807 CHEBI:88339 inhibits GO:0007049 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Therefore, these results indicated that dasatinib in combination with BMS-754807 arrested cell cycle in the G1/S transition by affecting CDK4/CDK6/CyclinD1 function. 1 BMS-754807 CHEBI:88339 activates GO:0007049 Phenotype 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 "Additional studies are under way to help clarify the observed cell line–dependent differences in cell cycle phenotypes caused by BMS-754807 (25)." 1 BMS-754807 CHEBI:88339 activates GO:0007049 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 causes cell cycle G1 phase arrest in lung cancer cells. 1 BMS-754807 CHEBI:88339 activates MESH:D002945 Phenotype 82e632ea-3406-11e8-9fbf-001a4a160176 PMC5610669 Moreover, BMS-754807 has been shown to sensitize MCF7 breast cancer cells to inhibitors of ataxia telangiectasia-mutated and RAD3-related kinase (ATR), both of which mediate DNA damage repair, and to potentiate the effects of cisplatin in some cell lines [164]. 1 BMS-754807 CHEBI:88339 activates MESH:D002945 Phenotype 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 At all concentrations of cisplatin and carboplatin used, the addition of BMS-754807 enhanced the effects of cisplatin and carboplatin (Fig.5a, b). 1 BMS-754807 CHEBI:88339 activates GO:0007050 Phenotype 84acb41e-c776-11ee-8b99-0050569a1f61 10.1016/j.ejmech.2023.115495 In H460 xenografted mice model, combination of BMS-754807 (6.25 mg/kg, oral administration) and 2-deoxyglucose (6.25 mg/kg, oral administration) suppressed 69.0% tumor growth without great influence on body weight and restored G2/M phase cell cycle arrest, while the tumor growth was not apparently inhibited in monotherapy [39]. 1 BMS-754807 CHEBI:88339 activates GO:0007050 Phenotype ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 In PC-3 and LNCaP cells, treatment with the combination of dasatinib and BMS-754807 increased cell cycle arrest and cell death, relative to either inhibitor alone (Fig. 1B). 1 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype f81f4c58-351a-11e8-a51f-001a4a160176 28236033 For ER+ ZR-75-30 cells, single agent BMS-754807 did cause a moderate increase in apoptosis above background (Fig.5), which was slightly higher when combined with trastuzumab, neratinib, or fulvestrant, and marginally higher for the BMS-754807/neratinib/fulvestrant triplet. 1 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype 18c6658e-c472-11e5-9da3-001a4ae51247 19996272 In addition, BMS-754807 induced greater apoptosis in Rh41 cells by 24 hours as indicated by an increased sub-G1peak (23.1%), compared with control (2.4%) or mAb391 (13.4%). 1 BMS-754807 CHEBI:88339 activates GO:0006915 Phenotype 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 BMS-754807 significantly increase apoptosis in both A549 and NCI-H358 cells and significantly reduced proliferation in A549 cells. 1 BMS-754807 CHEBI:88339 inhibits MESH:D000860 Phenotype 1fb262bc-ede4-11e5-9b35-001a4ae51246 26187851 As shown insupplementary material Fig. S2D,E, K252a and BMS-754807 significantly inhibited the Ca2+elevation, indicating that the Trk receptors, IGF-1R and insulin receptor play a role in the hypoxia-induced intracellular Ca2+elevation. 1 BMS-754807 CHEBI:88339 inhibits GO:0007165 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Overall, these results suggested that dasatinib in combination with BMS-754807 mainly blocked the PI3K/Akt/mTOR signaling pathway in a dose-dependent manner in lung cancer cells. 1 BMS-754807 CHEBI:88339 inhibits MESH:D001835 Phenotype 84acb41e-c776-11ee-8b99-0050569a1f61 10.1016/j.ejmech.2023.115495 In OE19 esophageal adenocarcinoma cell-derived subcutaneous xenografted mice model, BMS-754807 (25 mg/kg, intraperitoneal injection) exhibited a significant tumor regression response to 62.4% and suppressed 52.0% tumor growth without any significant change in mice body weight. 1 BMS-754807 CHEBI:88339 inhibits GO:0016049 Phenotype e6778eca-5cbc-11e7-af4d-001a4ae51247 PMC4674309 Despite this potent inhibitory activity toward IGF-IR, the BMS-754807 IC50values to inhibit cell growth in MDA-MB-468 and MDA-MB-231 cells were much higher than those of KW-2450 (IC50sof BMS-754807: 2.91 and 2.27 μmol/L for MDA-MB-468 and MDA-MB-231 cells, respectively). 1 BMS-754807 CHEBI:88339 inhibits GO:0016049 Phenotype 7964fd04-f597-11eb-9801-001a4a160176 31042587 For example, the IGF1R inhibitors BMS-536924 and BMS-754807 decreased cell growth and reduced the survival of human T-ALL cell lines and primary T-ALL cells [12], similarly to PI3K/AKT/mTOR inhibitors [13,14]. 1 BMS-754807 CHEBI:88339 inhibits GO:0016049 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Herein, we demonstrated that dasatinib in combination with BMS-754807 inhibited lung cancer cell growth, while induced autophagy as well as cell cycle arrest at the G1 phase. 1 BMS-754807 CHEBI:88339 inhibits MESH:D002470 Phenotype daeb38b8-c465-11e5-9cbe-001a4ae51247 23578138 Effect of BMS-754807 on proliferation: BMS-754807 dose-dependently inhibited live cells (cell viability), increasing dead cells (cytotoxicity) via apoptosis (caspase 3/7 activation; Fig.8c,d). 1 BMS-754807 CHEBI:88339 inhibits MESH:D002470 Phenotype 6f87527e-f592-11eb-8eab-001a4a160175 PMC7054265 BMS-754807 inhibited cell survival at ≥100 nM in aHGG cells and 10–30 nM in pHGG (Fig.2c), but only DK-MG and KNS42 had SF50values within the 5–365 nM range.8To test effects on radiosensitivity, cells were pre-treated for 4 h with 300 nM BMS-754807 prior to irradiation. 1 BMS-754807 CHEBI:88339 inhibits GO:0006914 Phenotype d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 This study revealed that the Src inhibitor dasatinib in combination with the IGF-1R inhibitor BMS-754807 induced autophagy, and simultaneously suppressed lung cancer cell viability by cell cycle arrest. 1 BMS-754807 CHEBI:88339 activates MESH:D000077289 Phenotype f81f4c58-351a-11e8-a51f-001a4a160176 28236033 Hou et al. have reported that BMS-754807 synergizes in vitro and in vivo with tamoxifen, letrozole, or fulvestrant in breast cancer models [65]; in addition, the combination resulted in upregulation of HER2, EGFR, and HER4, supporting our proposal that triple-targeting, and inhibiting the entire HER axis, would be of benefit. 1 BMS-754807 CHEBI:88339 activates FPLX:PI3K ProteinFamily 298aa5d0-c47a-11e5-85e4-001a4ae51246 21266413 Pharmacological inhibition of IGF signaling NVP-AEW541 and BMS-754807, LY294002 and U0126 were used to inhibit the Igf1r, PI3K and Mek1/2 activities, respectively. 1 BMS-754807 CHEBI:88339 inhibits FPLX:ERK ProteinFamily 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Evaluation of target proteins in tumor lysates showed that BMS-754807 treatment decreased levels of the activated form of IGF-1R/IR and downstream effectors AKT and ERK, and induced levels of the apoptosis related proteins cleaved caspase-3 and cleaved PARP-1, indicating that the BMS-754807 therapy is indeed managing to sufficiently affect these targets within the local tumor model. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:ERK ProteinFamily 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 Our findings showed that BMS-754807 significantly inhibited IGF-IR/IR, AKT and ERK1/2 phosphorylation and reduced the survival of both NSCLC cell lines evaluated. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:ERK ProteinFamily 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Western blot analysis Inhibition of IGF-1R and insulin receptor phosphorylation and ERK/Akt pathways by BMS-754807 alone or combination with 4-OH tamoxifen (10 μmol/L), letrozole (10 μmol/L), or fulvestrant (100 nmol/L) were determined by Western blotting. 1 BMS-754807 CHEBI:88339 activates FPLX:MEK ProteinFamily 298aa5d0-c47a-11e5-85e4-001a4ae51246 21266413 Pharmacological inhibition of IGF signaling NVP-AEW541 and BMS-754807, LY294002 and U0126 were used to inhibit the Igf1r, PI3K and Mek1/2 activities, respectively. 1 BMS-754807 CHEBI:88339 decreases FPLX:Cyclin ProteinFamily d0c97cf8-77a1-11ee-ae93-0050569a1f61 10.1007/s10637-023-01360-9 Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:AKT ProteinFamily 3fa4afcc-eda2-11e5-9b35-001a4ae51246 PMC4772483 Our findings showed that BMS-754807 significantly inhibited IGF-IR/IR, AKT and ERK1/2 phosphorylation and reduced the survival of both NSCLC cell lines evaluated. 1 BMS-754807 CHEBI:88339 inhibits FPLX:AKT ProteinFamily 1a6d3574-3791-11e6-8a17-001a4ae51247 PMC5216918 Evaluation of target proteins in tumor lysates showed that BMS-754807 treatment decreased levels of the activated form of IGF-1R/IR and downstream effectors AKT and ERK, and induced levels of the apoptosis related proteins cleaved caspase-3 and cleaved PARP-1, indicating that the BMS-754807 therapy is indeed managing to sufficiently affect these targets within the local tumor model. 1 BMS-754807 CHEBI:88339 decreases FPLX:AKT ProteinFamily f81f4c58-351a-11e8-a51f-001a4a160176 28236033 However, the addition of BMS-754807 to either trastuzumab or neratinib elicited the greatest suppression of levels of phospho-ERK and- Akt in both cell lines. 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:AKT ProteinFamily 4d8c8efe-c479-11e5-a92e-001a4ae51246 PMC4004036 Western blot analysis Inhibition of IGF-1R and insulin receptor phosphorylation and ERK/Akt pathways by BMS-754807 alone or combination with 4-OH tamoxifen (10 μmol/L), letrozole (10 μmol/L), or fulvestrant (100 nmol/L) were determined by Western blotting. 1 BMS-754807 CHEBI:88339 activates FPLX:AKT ProteinFamily be570ba0-c46f-11e5-91a7-001a4ae51247 PMC4122288 "Although the IGF1R/IR inhibitor BMS-754807 repressed AKT activation at low nanomolar doses, it failed to efficiently inhibit the mTORC1 substrate S6K1 at these concentrations and impacted viability only at doses that were 2 orders of magnitude higher." 1 BMS-754807 CHEBI:88339 inhibits FPLX:AKT ProteinFamily e5bdeaf4-c485-11e5-a92e-001a4ae51246 23047891 "Evaluation of target proteins in tumor tissue lysates showed that BMS-754807 treatment decreased levels of the activated form of IGF-1R and AKT, and induced levels of apoptosis-related proteins, indicating that the BMS-754807 therapy is indeed managing to affect these targets within the local tumor model." 1 BMS-754807 CHEBI:88339 activates FPLX:AKT ProteinFamily ee955064-bc37-11e5-8d2d-001a4ae51247 PMC3530555 Thus, the combination of dasatinib and BMS-754807 decreases survival in part, due to complete inhibition of Akt. 1 BMS-754807 CHEBI:88339 phosphorylatesProtein FPLX:AKT ProteinFamily a5af49fe-ae93-11ec-8f68-0050569a1f61 PMC8732810 Effective inhibition of ligand-stimulated phosphorylation of IGF receptors and Akt by BMS-754807 in serum-free medium was confirmed in SNU-1 and NUGC3 (Fig. 2e). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:AKT ProteinFamily dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 Second, 2-DG-induced AKT phosphorylation can be significantly attenuated by BMS-754807 in NSCLC. 1 BMS-754807 CHEBI:88339 inhibits FPLX:AKT ProteinFamily 11bad6f0-66f0-11e6-a7ed-001a4ae51246 PMC4988785 In contrast to CP-751,871, we noted that BMS-754807 suppressed activation of AKT by both IGF1 and IL-7, indicating a degree of cross-reactivity on IL7R/JAK at the 0.5 μM dose (Fig 7C). 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:AKT ProteinFamily be570ba0-c46f-11e5-91a7-001a4ae51247 PMC4122288 "BMS-754807 alone or in combination with PD-0332991 reduced tyrosine autophosphorylation of IGF1R/IR as well as phosphorylation of the IGF1R/IR downstream effector AKT (Fig. 3B)." 1 BMS-754807 CHEBI:88339 dephosphorylatesProtein FPLX:mTORC1 ProteinFamily ab1815b8-3905-11e8-a51f-001a4a160176 28062706 Similar to rapamycin (mTORC1 inhibitor) and torin (dual mTORC1 and mTORC2 inhibitor), the PKC412/BMS-754807 combination inhibited activation of the mTOR pathway, demonstrated by its hallmark phosphorylation of a downstream TORC1 effector p70S6 kinase (S6K) at the threonine residue 389 (T389;Fig. 4C). 1 BMS-754807 CHEBI:88339 inhibits FPLX:INSR ProteinFamily 937c4e38-c75c-11ee-b346-0050569a791b 10.1016/j.compbiolchem.2023.107934 Insulin receptor family kinases are effectively and irreversibly inhibited by the drug BMS-754807. 1 UNIPROT:P01308 activates BMS-754807 CHEBI:88339 Protein 4a0a0db4-c47f-11e5-85e4-001a4ae51246 PMC3073089 However, insulin levels increased from 0.5 to 110 ng/mL after 14 days of treatment with BMS-754807 alone (adjustedP< 0.0001; Supplementary Fig. S4D). 1 UNIPROT:P06213 activates BMS-754807 CHEBI:88339 Protein 2c743536-c47f-11e5-85e4-001a4ae51246 20807811 IR is not expressed in all cell lines and may not contribute to the resistance to either BMS-754807 or MAB391. 1 GO:0042769 inhibits BMS-754807 CHEBI:88339 Phenotype f18a81de-5801-11e6-8f02-001a4ae51247 PMC5302955 MCF-7 cells resistant to BMS-754807 accumulate γH2AX and are sensitive to dual kinase inhibition of IGF-1R and ATR Noting the potential therapeutic benefit of dual inhibition of IGF-1R and ATR, we next investigated whether the DDR contributes to resistance to the IGF-1R inhibitor BMS-754807. 1 UNIPROT:Q53EL6 inhibits BMS-754807 CHEBI:88339 Protein 269146f8-ee1a-11e5-872c-001a4ae51246 PMC4456303 "Conversely, knockdown of Pdcd4 in HT29 cells abolished the growth inhibitory effect of BMS-754807." 1 UNIPROT:Q15831 inhibits BMS-754807 CHEBI:88339 Protein dd9c2165-dc7a-11ea-a432-001a4a160175 PMC6447049 We also evaluated whether the restoration of wild-type LKB1 abolished the combined effect of 2-DG and BMS-754807 in EKVX isogenic cell lines. 1 MESH:D012822 activates BMS-754807 CHEBI:88339 Phenotype 4acb8656-bc1e-11e5-9b9d-001a4ae51247 10.1016/j.jchromb.2010.04.018 Conclusion The use of bare (unbonded) silica column enabled the retention of both BMS-754807 and metformin for the development of a LC–MS/MS-based bioanalytical method for the simultaneous quantitation of the two compounds in rat plasma.