S49076 is a novel kinase inhibitor of MET, AXL and FGFR with strong preclinical activity alone and in association with bevacizumab.

Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Leonce S, Ferry G, Da Violante G, Bouzom F, Cattan V, Jacquet-Bescond A, Comoglio PM, Lockhart BP, Boutin JA, Cordi A, Ortuno JC, Pierre A, Hickman JA, Cruzalegui FH, Depil S.
Journal   Mol Cancer Ther.
Species  
Analytes Measured   Akt , Met , p70S6K
Matrix Tested   Cell lysates
Year   2013
Volume  
Page Numbers  
Application   Phosphoproteins
Abstract
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 anti-cancer 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, 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. Based on these preclinical studies showing a favorable and novel pharmacological profile of S49076, a phase I study is currently underway in patients with advanced solid tumors.

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