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|Ref Type||Journal Article|
|Authors||Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Léonce S, Ferry G, Da Violante G, Bouzom F, Cattan V, Jacquet-Bescond A, Comoglio PM, Lockhart BP, Boutin JA, Cordi A, Ortuno JC, Pierré A, Hickman JA, Cruzalegui FH, Depil S|
|Title||S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|S-49076||S49076||Aurkb Inhibitors 20 AXL Inhibitor 27 FGFR1 Inhibitor 23 FGFR2 Inhibitor 16 FGFR3 Inhibitor 13 MET Inhibitor 51||S-49076 is a multi-kinase inhibitor that inhibits wild-type and mutant forms of MET and FGFR1-2, as well as FGFR3, AXL, MER, and AURKB, resulting in decreased downstream signaling, and potentially resulting in decreased tumor growth (PMID: 23804704, PMID: 28624695, PMID: 28619752).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR3 - TACC3||urinary bladder cancer||predicted - sensitive||S-49076||Preclinical||Actionable||In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 23804704, PMID: 23175443).||23175443 23804704|
|Unknown unknown||colon carcinoma||not applicable||Bevacizumab + S-49076||Preclinical - Cell line xenograft||Actionable||In a preclinical study, S-49076, in combination with Avastin (bevacizumab) arrested tumor growth in cell line xenograft models of colon carcinoma with previous resistance to Avastin (bevacizumab) (PMID: 23804704).||23804704|
|FGFR3 act mut||urinary bladder cancer||predicted - sensitive||S-49076||Preclinical||Actionable||In a preclinical study, S-49076 inhibited autophosphorylation of FGFR3 and downstream signaling in bladder cancer cells over expressing constitutively active FGFR3 in culture (PMID: 23804704).||23804704|
|FGFR2 act mut||stomach carcinoma||sensitive||S-49076||Preclinical - Cell line xenograft||Actionable||In a preclinical study, S-49076 inhibited Met activation, resulting in growth inhibition of gastric carcinoma cells harboring FGFR2 activating mutations in culture and in cell line xenograft models (PMID: 23804704).||23804704|