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

• Published in: Molecular cancer therapeutics 2013-09, Vol.12 (9), p.1749-1762
• Main Authors: Burbridge, Mike F, Bossard, Céline J, Saunier, Carine, Fejes, Imre, Bruno, Alain, Léonce, Stéphane, Ferry, Gilles, Da Violante, Georges, Bouzom, François, Cattan, Valérie, Jacquet-Bescond, Anne, Comoglio, Paolo M, Lockhart, Brian P, Boutin, Jean A, Cordi, Alex, Ortuno, Jean-Claude, Pierré, Alain, Hickman, John A, Cruzalegui, Francisco H, Depil, Stéphane
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Bevacizumab; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Female; Humans; Indoles - chemistry; Indoles - pharmacology; Mice; Mice, Inbred BALB C; Neoplasms - drug therapy; Neoplasms - pathology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0075

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.