Abstract 797: Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy

Abstract c-MET is a receptor tyrosine kinase that is dysregulated in several types of maliganacies, including gastric, liver and lung cancers. Abnormal activation of c-MET could be caused by gene amplification, overexpression, or HGF aberrant expression. Activation of c-MET is involved in several cellular processes, including cell proliferation, cell migration, and angiogenesis. To explore c-MET targeted therapy, we discovered a small molecule that selectively inhibits c-MET activity with an IC50 of single digit nanomolar concentration across several cell lines. In xenograft tumor models from cell lines harboring cMET amplification including liver, gastric and lung cancer, tumor growth was significantly inhibited by this compound in a dose dependent manner. In addition, PD studies showed that c-MET and down-stream signaling pathways were blocked by the compound in the cMET amplified tumors. The compound also showed desirable PK and safety profiles. These data warrants further development of this compound for cancer therapy in cMET dysregulated cancers. Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 797. doi:10.1158/1538-7445.AM2015-797