Despite the vigorous activity in the development of c-Met inhibitors, none of the c-Met inhibitors or c-Met pathway antagonists has been approved for clinical use. Notably, most of the reported c-Met kinase inhibitors across the clinical trials lack selectivity and target multiple kinases, which will likely result in unwanted off-target toxicities. The discovery of highly selective c-Met inhibitors may represent an important direction to increase chances of targeting c-Met for cancer therapy. Simm559 is identified as a highly selective and potent c-Met inhibitor, with IC50 = 0.24 ± 0.04 nM against c-Met kinase, while it barely inhibited kinase activity of a panel of tyrosine kinases, including c-Met family member and its highly homologous kinases. Simm559 significantly inhibited c-Met-driven cell proliferation, in particular c-Met constitutively activated NSCLC and gastric cancer cells, with an average IC50 at 0.66 nM. Such potency was over 10,000-fold of that in cells with low c-Met expression or activity. Oral dosing of Simm559 at 25 mg/kg (BID) resulted in significant antitumor activity in several c-Met-driven xenograft models, especially in NSCLC EBC-1 xenograft, gastric SNU5 xenograft and a patient-derived NSCLC xenograft model with MET amplification. Complete tumor regressions were observed in both cell line-based and patient-derived lung cancer xenograft models. Safety evaluation and pharmacokinetic analysis showed that Simm559 is safe and well tolerant with acceptable pharmacodynamic properties. All these evidence promise Simm559 as a therapeutic candidate for c-Met-driven human cancers.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B285.

Citation Format: Jing Ai, ZhengSheng Zhan, Ying Wang, Fang Chen, Xia Peng, Yi Chen, Yinchun Ji, Jian Ding, Meiyu Geng, Wenhu Duan. A novel, potent, highly selective inhibitor of c-Met kinase, Simm559, inhibits c-Met-dependent neoplastic phenotypes in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B285.