count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 4 momelotinib CHEBI:91407 activates GO:0030154 Phenotype 17fbaadc-e9df-11ef-b5b7-0050569a1f61 10.1182/bloodadvances.2024014046 Two other JAK inhibitors, fedratinib and momelotinib, similarly reduced the expansion and differentiation of ESLAM HSCs in culture (supplemental Figure 5I-J). 4 momelotinib CHEBI:91407 activates MESH:D055728 Phenotype ce266d40-1bf5-11f0-a2ca-0050569a1f61 10.1016/j.apsb.2023.12.010 Momelotinib was shown to produce clinically significant improvements in spleen response, anemia, and myelofibrosis-associated symptoms than the traditional danazol treatment, which supported momelotinib as an effective treatment option in patients with myelofibrosis, especially in those with anemia210. 4 momelotinib CHEBI:91407 activates MESH:D000740 Phenotype e08cf55a-374e-11e8-bf76-001a4a160175 28028027 Momelotinib, a JAK1 and JAK2 inhibitor, produced anemia responses in addition to improvements in spleen and symptom burden.67,68Intriguingly, multivariate analysis suggested best responses occurred inCALR+/ASXL1−patients.69Peripheral neuropathy was reported and may be important in deciding where momelotinib sits in the therapeutic algorithm. 4 momelotinib CHEBI:91407 activates MESH:D000740 Phenotype ce266d40-1bf5-11f0-a2ca-0050569a1f61 10.1016/j.apsb.2023.12.010 Momelotinib was shown to produce clinically significant improvements in spleen response, anemia, and myelofibrosis-associated symptoms than the traditional danazol treatment, which supported momelotinib as an effective treatment option in patients with myelofibrosis, especially in those with anemia210. 4 momelotinib CHEBI:91407 inhibits UNIPROT:P01106 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 In the first group of patients, MYC was reduced by both momelotinib and ruxolitinib to similar extents, indicating that MYC expression is most likely modulated by Jak-mediated signaling in those samples (Figure 5B).|||To further confirm that MYC inhibition by momelotinib is mediated through inhibition of IKBKE, we knocked down IKBKE or TBK1 in AML cells using RNA interference.|||Using an MYC mini-signature gene list,27we also directly validated that the MYC transcriptional program was inhibited by momelotinib treatment (Figure 3D).|||In integrating these 2 analyses, it became clear that gene sets representing the MYC transcriptional program were specifically enriched in cell lines that are sensitive to IKBKE/TBK1 inhibition (Figure 3A) and that the MYC transcriptional program was inhibited by momelotinib. 4 MESH:D003613 activates momelotinib CHEBI:91407 Phenotype ce266d40-1bf5-11f0-a2ca-0050569a1f61 10.1016/j.apsb.2023.12.010 Momelotinib was shown to produce clinically significant improvements in spleen response, anemia, and myelofibrosis-associated symptoms than the traditional danazol treatment, which supported momelotinib as an effective treatment option in patients with myelofibrosis, especially in those with anemia210. 3 momelotinib CHEBI:91407 activates GO:0006915 Phenotype b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Furthermore, apoptosis induced by momelotinib treatment was suppressed by LKB1 re-expression in KL A549 cells (Figure S1F).|||Indeed, single-agent momelotinib treatment induced apoptosis in KL and KLP but not in KP cells (Figure 1B).|||Indeed, linsitinib treatment potently induced apoptosis together with lower concentrations of momelotinib that were unable to induce apoptosis in A549 cells (Figures 2J andS2L). 2 momelotinib CHEBI:91407 activates UNIPROT:P81172 Protein b1f57544-351b-11e8-b868-001a4a160176 PMC5755682 In vivo, the administration of the ALK2 inhibitor momelotinib strongly suppresses hepcidin activation in rats with anemia of inflammation,44with documented increased hepatic SMAD1/5/8 phosphorylation,38whereas it is ineffective in basal condition.44These results suggest that in inflammation ALK2 is functional and not bound to FKBP12. 2 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein 5f753334-3388-11e8-a34b-001a4a160175 27106071 Interestingly, momelotinib also inhibits activin receptor-like kinase-2 (ALK2) which is known to regulate expression of hepcidin. 2 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein b656bf82-ae96-11ec-b4ed-0050569a1f61 PMCPMC8772195 In accordance with momelotinib-driven inhibition of ACVR1/ALK2, induction of phosphorylated SMAD1/5/8 decreased in BMP6-stimulated HepG2 cells when momelotinib was added [66]. 2 momelotinib CHEBI:91407 activates MESH:D000740 Phenotype b1f57544-351b-11e8-b868-001a4a160176 PMC5755682 In vivo, the administration of the ALK2 inhibitor momelotinib strongly suppresses hepcidin activation in rats with anemia of inflammation,44with documented increased hepatic SMAD1/5/8 phosphorylation,38whereas it is ineffective in basal condition.44These results suggest that in inflammation ALK2 is functional and not bound to FKBP12. 2 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein f2869c26-abd7-11eb-8312-001a4a160175 PMCPMC8146033 Momelotinib is a selective inhibitor of JAK1, JAK2, and ACVR1 which is being developed in anemic MF patients [20].|||In preclinical models, inhibition of ACVR1 by momelotinib leads to decreased hepcidin production, which mobilizes sequestered iron and improves erythropoiesis [21]. 2 momelotinib CHEBI:91407 dephosphorylatesProtein UNIPROT:P67809 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 We found that LY294002 completely inhibited AKT phosphorylation, but had almost no effect on YB-1 phosphorylation; by contrast, momelotinib completely abolished YB-1 phosphorylation whereas having minimal effects on AKT phosphorylation (Figure 4C).|||We observed a very high correlation between the inhibition of YB-1 phosphorylation by momelotinib and reduction in MYC expression. 2 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Momelotinib is a potent inhibitor of JAK1 and JAK2.|||Momelotinib (CYT387) is an orally administered drug that inhibits JAK1, JAK2, JAK3, and TYK2 kinases [22,23–24]. 2 momelotinib CHEBI:91407 inhibits UNIPROT:P23458 Protein eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Momelotinib (CYT387) is an orally administered drug that inhibits JAK1, JAK2, JAK3, and TYK2 kinases [22,23–24].|||Momelotinib is a potent inhibitor of JAK1 and JAK2. 2 momelotinib CHEBI:91407 inhibits UNIPROT:Q9UHD2 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 It should also be noted that momelotinib inhibits TBK1 with a 50% inhibitory concentration in the high nanomolar range in in vitro assays.24This matches the effective concentrations of momelotinib in the IKBKE-sensitive AML cells.|||To further narrow down the gene sets and corresponding signaling pathways that are modulated by IKBKE, we then carried out gene expression profiling to determine global transcriptome changes upon IKBKE/TBK1 inhibition induced by momelotinib in 2 sensitive AML cell lines. 2 momelotinib CHEBI:91407 decreases UNIPROT:P01106 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 Expression of this construct rescued the inhibition of MYC expression induced by momelotinib treatment (Figure 4J) and largely rescued the induction of apoptosis mediated by this drug (Figure 4K).|||In the second group, momelotinib decreased MYC expression to a much greater extent than ruxolitinib, suggesting that MYC is likely modulated largely by IKBKE/TBK1 in these samples. 2 UNIPROT:P05231 activates momelotinib CHEBI:91407 Protein 89cc8f24-3757-11e8-9fbf-001a4a160176 PMC5028268 Whereas deletion of IL-6 alone disrupted the inflammatory microenvironment and limited PanIN progression[22], similar to treatment with momelotinib[47], inhibition of MEK alone using the kinase inhibitor PD325901 was able to suppress PanIN growth, but did not prevent pancreatitis[73]. 2 UNIPROT:P46937 activates momelotinib CHEBI:91407 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 YAP1 Activation Mediates Intrinsic Resistance to Momelotinib and MEK Inhibitor Treatment in KP Cells Since KP cells were relatively insensitive to momelotinib treatment, we also considered the possibility that activation of similar pathways at baseline could contribute to intrinsic resistance to JAK/TBK1 inhibition.|||To elucidate whether higher YAP1 expression in KP cells contributes to intrinsic resistance to momelotinib, we established YAP1-depleted KP cells (Figure S5C). 1 momelotinib CHEBI:91407 activates UNIPROT:Q9UEF7 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Indeed, single-agent momelotinib treatment induced apoptosis in KL and KLP but not in KP cells (Figure 1B). 1 momelotinib CHEBI:91407 activates UNIPROT:P42229 Protein c1ec9c98-351f-11e9-913f-001a4a160175 PMC6286697 Incubation ofCBLmyeloid cells with JAK inhibitors momelotinib or ruxolitinib significantly decreased pJAK2 and pSTAT5, while minimal or no effects of JAK inhibition were observed inPTPN11or control cells (Figure 3C). 1 momelotinib CHEBI:91407 decreases UNIPROT:P81172 Protein 479ce7d2-6fb1-11ee-ae93-0050569a1f61 10.1007/s11899-023-00702-x A phase 2 study demonstrated that momelotinib causes an abrupt reduction in hepcidin levels, consistent with the BMP receptor ACVR1-mediated inhibition of hepcidin expression. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P81172 Protein 062bbe88-ae95-11ec-b4ed-0050569a1f61 PMCPMC8431305 Momelotinib, apart from being an JAK1/2 inhibitor, antagonizes the effects of hepcidin; therefore, it is thought to become useful in MF with transfusion-requiring anemia. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P81172 Protein bb4ee634-3d1a-11f0-8978-0050569a1f61 PMC7509854 " • Momelotinib inhibited hepcidin, an iron-regulatory hormone associated with restricted erythropoiesis." 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein bdb72b42-c78d-11ee-ae05-0050569a1f61 10.1016/j.intimp.2023.110660 Compared with ruxolitinib, momelotinib inhibits ACVR1, which leads to the reduction of ferrimodulin. 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein 30f6ac52-8cbc-11ee-add2-0050569a791b 10.1007/s11030-023-10742-3 The pharmacological mechanism of Jaktinib is similar to that of Momelotinib, as it may also inhibit ACVR1 and improve anemia. 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein fb98639c-e720-11ee-b346-0050569a791b 10.1007/s00277-024-05703-1 Momelotinib, a JAK1, JAK2, and ACVR1 inhibitor, inhibits ACVR1-mediated ferroportin production, increases serum iron utilization and stimulates red blood cell production [61]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein 5c6b5f38-c739-11ee-8b99-0050569a1f61 PMC10561048 Momelotinib inhibited ACVR1 with a mean IC50of 52.5 nM, which is ∼3.2 times lower than the clinical unbound Cmaxbased on 200 mg daily dosing. 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein 698bfde5-f57c-11eb-8690-001a4a160175 PMC7809704 Momelotinib (Sierra Oncology) is a selective inhibitor of JAK1, JAK2, and ACVR1 which has been evaluated in two phase III trials. 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q04771 Protein 0103657c-72e9-11ee-add2-0050569a791b 10.1007/s12254-023-00906-0 Momelotinib is a selective inhibitor of JAK1/2 and ACVR1 [14,15]. 1 momelotinib CHEBI:91407 phosphorylatesProtein UNIPROT:P08069 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 In A549 cells, momelotinib treatment for 24 hr increased phosphorylation of IGF1 receptor (IGF1R), in contrast to the JAK1/2-specific inhibitor ruxolitinib (Figure S2A). 1 momelotinib CHEBI:91407 phosphorylatesProtein UNIPROT:P67809 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 Furthermore, the kinetics of the decrease in MYC mRNA induced by IKBKE inhibitors overlaps with the changes induced by compounds that inhibit MYC transcription, such as JQ1 and actinomycin D. Finally, ChIP analysis demonstrated that YB-1 binds directly to theMYCpromoter, and this binding is disrupted upon inhibition of YB-1 phosphorylation by momelotinib treatment. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P67809 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 As noted, YB-1 inhibition by either momelotinib treatment or RNA interference leads to reduction of MYC mRNA levels, suggesting that YB-1 modulates MYC transcription. 1 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein 698bfde5-f57c-11eb-8690-001a4a160175 PMC7809704 Momelotinib (Sierra Oncology) is a selective inhibitor of JAK1, JAK2, and ACVR1 which has been evaluated in two phase III trials. 1 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein 212a3a26-c689-11ee-b22c-0050569a1f61 10.1016/j.bbcan.2023.189054 Josset et al. found that mTOR inhibitor everolimus increased cytotoxic effect of TMZ and radiation in U87 cells via augmented autophagic cell death [59], while Liu et al. showed that momelotinib inactivated JAK2/STAT3 signaling pathway resulting in enhanced autophagy and higher sensitivity of U251 cells to TMZ [134]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein 4cca9c62-c6ba-11ee-b346-0050569a791b 10.1016/j.ejmech.2023.115848 Momelotinib is a potent inhibitor of JAK1 (IC50= 11 nM) and JAK2 (IC50= 18 nM). 1 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein f2869c26-abd7-11eb-8312-001a4a160175 PMCPMC8146033 Momelotinib is a selective inhibitor of JAK1, JAK2, and ACVR1 which is being developed in anemic MF patients [20]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:O60674 Protein 0d8883ea-ae96-11ec-89b1-0050569a791b PMCPMC8617206 In murine models, momelotinib is unable to completely eliminate JAK2-dependent cells, and MPN often reappears, suggesting that it is not curative and is better used in combinational therapy. 1 momelotinib CHEBI:91407 activates UNIPROT:O60674 Protein c1ec9c98-351f-11e9-913f-001a4a160175 PMC6286697 Incubation ofCBLmyeloid cells with JAK inhibitors momelotinib or ruxolitinib significantly decreased pJAK2 and pSTAT5, while minimal or no effects of JAK inhibition were observed inPTPN11or control cells (Figure 3C). 1 momelotinib CHEBI:91407 inhibits UNIPROT:P29597 Protein eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Momelotinib (CYT387) is an orally administered drug that inhibits JAK1, JAK2, JAK3, and TYK2 kinases [22,23–24]. 1 momelotinib CHEBI:91407 activates UNIPROT:P78509 Protein eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 (* p < 0.001) Citarinostat + momelotinib combination induced sub-G0/G1 arrest in malignant hematological cells In WSU-NHL, Karpas-422, RL, and Jeko-1 cells, citarinostat (4 µM) alone induced a slight increase in the percentage of cells that entered the G0/G1 phase, compared to untreated cells. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P52333 Protein eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Momelotinib (CYT387) is an orally administered drug that inhibits JAK1, JAK2, JAK3, and TYK2 kinases [22,23–24]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P23458 Protein f2869c26-abd7-11eb-8312-001a4a160175 PMCPMC8146033 Momelotinib is a selective inhibitor of JAK1, JAK2, and ACVR1 which is being developed in anemic MF patients [20]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P23458 Protein 4cca9c62-c6ba-11ee-b346-0050569a791b 10.1016/j.ejmech.2023.115848 Momelotinib is a potent inhibitor of JAK1 (IC50= 11 nM) and JAK2 (IC50= 18 nM). 1 momelotinib CHEBI:91407 inhibits UNIPROT:P23458 Protein 698bfde5-f57c-11eb-8690-001a4a160175 PMC7809704 Momelotinib (Sierra Oncology) is a selective inhibitor of JAK1, JAK2, and ACVR1 which has been evaluated in two phase III trials. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P40763 Protein 1deecb5a-ae95-11ec-b4ed-0050569a1f61 PMC8739290 Momelotinib temporarily inhibited pSTAT3 shortly after dosing, but there was no correlation between the total plasma momelotinib concentration and pSTAT3 inhibition. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P40763 Protein 212a3a26-c689-11ee-b22c-0050569a1f61 10.1016/j.bbcan.2023.189054 Josset et al. found that mTOR inhibitor everolimus increased cytotoxic effect of TMZ and radiation in U87 cells via augmented autophagic cell death [59], while Liu et al. showed that momelotinib inactivated JAK2/STAT3 signaling pathway resulting in enhanced autophagy and higher sensitivity of U251 cells to TMZ [134]. 1 momelotinib CHEBI:91407 inhibits UNIPROT:P40763 Protein 03e0ce24-c76c-11ee-b346-0050569a791b PMC10577802 To disrupt the AXL-STAT3 signaling network, appropriate dosing schedules of dubermatinib (AXL inhibitor) and/or momelotinib (JAK1/2 inhibitor) were selected to minimize toxicity in mice (Figure S7D).22,44,45Repression of pSTAT3 by momelotinib in cancer cells was previously determinedin vitroand corroborated by western blotting (Figure S7E).44,46,47Compared to the control group, the momelotinib group displayed slightly larger tumor volumes (Figures 6B andS7F). 1 momelotinib CHEBI:91407 phosphorylatesProtein UNIPROT:P05019 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 In A549 cells, momelotinib treatment for 24 hr increased phosphorylation of IGF1 receptor (IGF1R), in contrast to the JAK1/2-specific inhibitor ruxolitinib (Figure S2A). 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q14164 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 To further narrow down the gene sets and corresponding signaling pathways that are modulated by IKBKE, we then carried out gene expression profiling to determine global transcriptome changes upon IKBKE/TBK1 inhibition induced by momelotinib in 2 sensitive AML cell lines. 1 momelotinib CHEBI:91407 decreases UNIPROT:Q14164 Protein b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 Consistent with findings in other cancer models,7prolonged treatment with momelotinib also reduced the total level of IKBKE as well (Figure 6G). 1 momelotinib CHEBI:91407 inhibits UNIPROT:Q9UHD2 Protein 16d3f424-350f-11e9-8325-001a4a160175 PMC6420784 •Although the activity observed with the momelotinib-trametinib combination at the doses evaluated did not improve on the historic data for single-agent trametinib, momelotinib concentrations were too low to inhibit TBK1; thus, the present findings did not invalidate the concept of combining a TBK1 inhibitor with a MEK1/MEK2 inhibitor, or for that matter, another agent targeting a keyKRASsignaling pathway. 1 momelotinib CHEBI:91407 activates UNIPROT:P49682 Protein 9e31091e-3b5c-11e8-b868-001a4a160176 PMC5993569 Ruxolitinib and the JAK1/JAK2 inhibitor momelotinib blocked upregulation of CXCR3 in wild-type T cells to a similar degree as deletion of IFNγ receptor[7]. 1 momelotinib CHEBI:91407 activates MESH:D059865 Phenotype eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Tubulin was used to normalize protein loading Citarinostat + momelotinib triggers ROS generation and promotes ER stress To clarify the mechanism of cell death induced by the combination treatment, we measured the levels of intrinsic oxidative stress in selected lymphoid cell lines. 1 momelotinib CHEBI:91407 activates MESH:D009369 Phenotype b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Because momelotinib and trametinib combination therapy already induced strong tumor regressions in the KL GEMM, there was no significant difference between two- and three-drug combinations at that point (Figure 6C). 1 momelotinib CHEBI:91407 activates MESH:D021441 Phenotype dfafab8c-c91f-11ee-b22c-0050569a1f61 10.1016/j.ejmech.2022.115034 Momelotinib (3), a JAK1/2 and TBK1 dual kinase inhibitor, can effectively inhibit the growth of NSCLC and pancreatic ductal carcinoma (PDAC) driven by KRAS mutations [20]. 1 momelotinib CHEBI:91407 activates MESH:D007501 Phenotype fb98639c-e720-11ee-b346-0050569a791b 10.1007/s00277-024-05703-1 Momelotinib, a JAK1, JAK2, and ACVR1 inhibitor, inhibits ACVR1-mediated ferroportin production, increases serum iron utilization and stimulates red blood cell production [61]. 1 momelotinib CHEBI:91407 inhibits MESH:D013163 Phenotype 286735f6-390d-11e8-8636-001a4a160175 27209535 Momelotinib reduced splenomegaly and reduced the severity of MF-associated anemia in mouse models of MPN and in patients [106–109]. 1 momelotinib CHEBI:91407 activates GO:0006915 Phenotype 0287c2ac-3759-11e8-a51f-001a4a160176 27473820 In pre-clinical studies, Tyner et al. found that between 0.5 and 1.5μM momelotinib produced growth suppression and apoptosis in JAK2-dependent human and murine hematopoietic cell lines, while non-hematopoietic cell lines were unaffected[83]. 1 momelotinib CHEBI:91407 activates GO:0006915 Phenotype 0d8883ea-ae96-11ec-89b1-0050569a791b PMCPMC8617206 Momelotinib induced growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines when added between 0.5 and 1.5 μM, without affecting nonhematopoietic cells. 1 momelotinib CHEBI:91407 activates GO:0006915 Phenotype eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 In the sensitive cell lines (WSU-NHL, RL, Karpas-422, Jeko-1, and L540) the citarinostat + momelotinib combination induced apoptosis mediated by the intrinsic (mitochondrial) apoptotic pathway. 1 momelotinib CHEBI:91407 activates GO:0008219 Phenotype eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Tubulin was used to normalize protein loading Citarinostat + momelotinib triggers ROS generation and promotes ER stress To clarify the mechanism of cell death induced by the combination treatment, we measured the levels of intrinsic oxidative stress in selected lymphoid cell lines. 1 momelotinib CHEBI:91407 activates GO:1903409 Phenotype eb8e43f5-dbc6-11ea-8563-001a4a160176 PMC7244621 Tubulin was used to normalize protein loading Citarinostat + momelotinib triggers ROS generation and promotes ER stress To clarify the mechanism of cell death induced by the combination treatment, we measured the levels of intrinsic oxidative stress in selected lymphoid cell lines. 1 momelotinib CHEBI:91407 activates MESH:D055728 Phenotype bb4ee634-3d1a-11f0-8978-0050569a1f61 PMC7509854 " Key Points • In a phase 2 study, momelotinib reversed or reduced transfusion dependency in transfusion-dependent myelofibrosis patients." 1 momelotinib CHEBI:91407 inhibits GO:0007165 Phenotype 212a3a26-c689-11ee-b22c-0050569a1f61 10.1016/j.bbcan.2023.189054 Josset et al. found that mTOR inhibitor everolimus increased cytotoxic effect of TMZ and radiation in U87 cells via augmented autophagic cell death [59], while Liu et al. showed that momelotinib inactivated JAK2/STAT3 signaling pathway resulting in enhanced autophagy and higher sensitivity of U251 cells to TMZ [134]. 1 momelotinib CHEBI:91407 inhibits MESH:D002470 Phenotype b555428c-34ed-11e9-8741-001a4a160176 PMC6290107 By contrast, in AML cell lines in which JAK/STAT signaling is not required for survival, momelotinib potently inhibits AML cell viability, whereas ruxolitinib has no effect (Figure 2E). 1 momelotinib CHEBI:91407 activates GO:0030218 Phenotype 5f753334-3388-11e8-a34b-001a4a160175 27106071 Increased erythropoiesis induced by momelotinib therapy may be mediated by reduction in hepcidin level via direct inhibition of ALK2 signaling. 1 momelotinib CHEBI:91407 activates GO:0030218 Phenotype b656bf82-ae96-11ec-b4ed-0050569a1f61 PMCPMC8772195 The aforementioned findings underscore the unique inhibitory activity of momelotinib on hepcidin expression and amelioration of iron-restricted anemia, thereby promoting erythropoiesis [66] under inflammation (such as in MF patients) as compared to agents that solely inhibit ACVR1 or JAK1/2. 1 momelotinib CHEBI:91407 inhibits MESH:D000077204 Phenotype 4e519676-ae93-11ec-8f68-0050569a1f61 PMCPMC8521049 The Janus kinase (JAK) inhibitor momelotinib (MTB) also potentiates TMZ efficacy via apoptosis and autophagy induction (240). 1 momelotinib CHEBI:91407 activates GO:0006914 Phenotype b36f4f4c-c789-11ee-9133-0050569a1f61 10.1016/j.biopha.2023.115187 The anti-cancer agents such as momelotinib stimulate autophagy via STAT3 suppression to increase TMZ response of glioblastoma[64]. 1 momelotinib CHEBI:91407 activates FPLX:RTK ProteinFamily b9015718-7935-11ee-add2-0050569a791b PMC10188327 Further examinations are assessing the effectiveness of new third generation of EGFR RTKIs (avitinib, rociletinib, nazartinib), non-selective RTKIs activating numerous RTKs, such as VEGF and EGF (momelotinib, anlotinib, sorafenib), or RTKIs that target the c-MET HGF (tepotinib, capmatinib), JAK2 (pacritinib, momelotinib), and AXL receptor tyrosine kinase (gilteritinib). 1 UNIPROT:P55957 activates momelotinib CHEBI:91407 Protein 245f65d2-7e83-11e6-b946-001a4ae51247 PMC5210237 BID dosing allowed for testing a higher total daily dose of momelotinib than QD dosing. 1 UNIPROT:P46937 inhibits momelotinib CHEBI:91407 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 YAP1-depleted KP cells showed higher sensitivity to momelotinib or MEK inhibitor treatment compared with control cells (Figures 5D andS5D). 1 CHEBI:91402 activates momelotinib CHEBI:91407 Chemical b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 As expected, linsitinib treatment clearly enhanced tumor shrinkage in response to intermittent momelotinib and trametinib dosing in KL GEMMs but not in KP GEMMs (Figures 2K,S2Q, and S2R). 1 CHEBI:91402 inhibits momelotinib CHEBI:91407 Chemical b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Addition of recombinant human IGF1 to parental A549 and H23 cells reduced cell growth inhibition following momelotinib treatment, which was completely antagonized by linsitinib treatment (Figures S2I and S2J). 1 UNIPROT:O60885 activates momelotinib CHEBI:91407 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Moreover, JQ1 treatment or genetic BRD4 depletion enhanced growth inhibition following momelotinib and MEK inhibitor combination treatment in parental A549 cells (Figures 4H, 4I, andS4D). 1 UNIPROT:Q8NFT8 activates momelotinib CHEBI:91407 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Intermittent BET Inhibitor Treatment Overcomes Resistance to Momelotinib/MEK Inhibition in KL and KP GEMMs Since BET inhibitor treatment broadly antagonized acquired resistance to momelotinib and MEK inhibitor therapy in KL cells and intrinsic resistance in KP cells, we explored the potential of higher order combination therapy as a strategy to achieve durable therapeutic responsesin vivo. 1 UNIPROT:P05019 inhibits momelotinib CHEBI:91407 Protein b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Addition of recombinant human IGF1 to parental A549 and H23 cells reduced cell growth inhibition following momelotinib treatment, which was completely antagonized by linsitinib treatment (Figures S2I and S2J). 1 FPLX:Hemoglobin activates momelotinib CHEBI:91407 ProteinFamily a710cd02-c7ed-11ee-8b99-0050569a1f61 PMC10368854 As previously reported, mean hemoglobin levels increased in each momelotinib-treated population, including patients in the control arms who had crossed over to receive momelotinib after week 24, and were maintained over time18,19,21Consistent with these improvements in mean hemoglobin levels, the incidence of anemia events (similar preferred terms) did not increase over time with momelotinib. 1 CHEBI:95080 activates momelotinib CHEBI:91407 Chemical b42cf138-dc71-11ea-a3f3-001a4a160175 PMC6422029 Moreover, JQ1 treatment or genetic BRD4 depletion enhanced growth inhibition following momelotinib and MEK inhibitor combination treatment in parental A549 cells (Figures 4H, 4I, andS4D).