Preclinical evaluation of WXSH0011, a selective small molecule dual inhibitor of FGFR/c-Met.

Abstract

e15641 Background: FGFRs (fibroblast growth factor receptors) are a family of receptor tyrosine kinases. c-Met is a receptor tyrosine kinase with a high-affinity ligand, hepatocyte growth factor/scatter factor (HGF/SF). Aberrations in the FGFR pathway are associated with a variety of human cancers. c-Met and HGF have been implicated in carcinogenesis and metastatic tumor progression because of their ability to enhance angiogenesis, cancer cell proliferation, migration, and invasion. WXSH0011 is an orally bioavailable novel potent and selective FGFR/c-Met dual kinase inhibitor, which displayed significant antitumor activity in preclinical models of solid cancer with FGFRs/c-Met overexpression. Preclinical studies demonstrated that WXSH0011 has potential to be effective in solid cancer, such as HCC and Gastric. Methods: Kinase inhibiting activity of WXSH0011 was determined with FGFRs/ c-Met kinase assays. Cellular anti-proliferative activity was evaluated with FGFR overexpressed NCl-H1581, SNU-16, RT112/84, Hep3B, c-Met overexpressed MHCC97H, EBC-1 cell line and FGFR, c-Met both overexpressed PDC cell line (LI-03-0141 (HCC) and ST-02-0063 (Gastric) PDC). The antitumor activity of WXSH0011 was evaluated in vivo cell derived-xenograft (CDX) models of Gastric Cancer SNU-16 and HCC Hep3B. Results: WXSH0011 displayed potent kinase inhibiting activity for FGFR1/2/3/4 and c-Met/ with IC50 0.19 nM/0.21 nM/1.15 nM/1.49 nM /15.9 nM, respectively. WXSH0011 inhibited cell proliferation in FGFR overexpressed NCl-H1581, SNU-16, RT112/84, Hep3B with IC50 10 nM, 3 nM, 2 nM, 63 nM, c-Met overexpressed MHCC97H and EBC-1 cell line with IC50 0.832 µM, 0.52 µM, FGFR, c-Met dual overexpressed LI-03-0141 (HCC) and ST-02-0063 (Gastric) PDC with IC50 0.19 µM, 0.08 µM. Kinome panel screening revealed that WXSH0011 demonstrated good overall kinase selectivity. WXSH0011 showed antitumor efficacy in gastric cancer SNU-16 (TGI = 100% @5 mpk, BID), as well as in the liver cancer Hep3B model (TGI = 86.92% @20 mpk, QD). Conclusions: We have identified a novel selective and potent dual FGFR/c-Met inhibitor WXSH0011. Preclinical studies shows antitumor efficacy of WXSH0011 in gastric and liver cancer models. It is currently at IND submission stage.