S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

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 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 METdriven 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.

MET/HGF targeted drugs as potential therapeutic strategies in non-small cell lung cancer

“…In combination with bevacizumab, S49076 achieved almost complete tumor growth arrest in colon carcinoma models [194]. Moreover, S49076 monotherapy arrested tumor growth in bevacizumab-resistant tumors [194].…”

“…Another multi-targeted inhibitor, S49076, has shown promising results against targets associated with resistance to EGFR or VEGFR [194]. In combination with bevacizumab, S49076 achieved almost complete tumor growth arrest in colon carcinoma models [194].…”

Clinical significance of MET in gastric cancer

“…S49076 decreased p-MET expression and cell viability in GTL16 cells. S49076 down-regulated p-MET, p-AKT, and phosphorylated p70S6K and inhibited tumor growth in a GTL16 xenograft model [61] . T-1840383 is a potent inhibitor that targets MET, VEGFR1-3, RET, RON, RSE, TIE2, and TRKA.…”

The Servier oncology pipeline in 2017

“…This molecule is an inhibitor of the MET, AXL and FGFR tyrosine kinase receptors, all of which have been implicated in resistance mechanisms in several tumor types [6,37]. Preclinical studies have shown that it selectively inhibits MET, AXL and FGFR signaling, affects the viability, motility and colony-forming ability of tumor cells expressing these tyrosine kinase receptors, and inhibits tumor growth [37].…”

“…This molecule is an inhibitor of the MET, AXL and FGFR tyrosine kinase receptors, all of which have been implicated in resistance mechanisms in several tumor types [6,37]. Preclinical studies have shown that it selectively inhibits MET, AXL and FGFR signaling, affects the viability, motility and colony-forming ability of tumor cells expressing these tyrosine kinase receptors, and inhibits tumor growth [37]. It has also shown activity in a xenograft model of colon carcinoma demonstrating acquired bevacizumab resistance and, when administered in combination with bevacizumab, can overcome the inherent resistance of CRCs to bevacizumab [37].…”