S49076 is a Novel Kinase Inhibitor of MET, AXL and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé S49076, un inhibiteur des signalisations MET, AXL/MER et FGFR1/2/3, seul ou en combinaison avec le bevacizumab
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.
http://mct.aacrjournals.org/content/early/2013/06/26/1535-7163.MCT-13-0075.abstract