Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities

// Ying Wang 1, * , Zhengsheng Zhan 2, * , Xifei Jiang 3, 4, * , Xia Peng 1 , Yanyan Shen 1 , Fang Chen 2 , Yinchun Ji 1 , Weiren Liu 3, 4 , Yinghong Shi 3, 4 , Wenhu Duan 2 , Jian Ding 1 , Jing Ai 1 , Meiyu Geng 1 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R.China 2 Department of Medicinal Chemistry Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R.China 3 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R.China 4 Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, P.R.China * These authors have contributed equally to this work Correspondence to: Jing Ai, e-mail: jai@simm.ac.cn Meiyu Geng, e-mail: mygeng@simm.ac.cn Keywords: c-Met, kinase inhibitor, Simm530 Received: October 29, 2015      Accepted: April 29, 2016      Published: May 13, 2016 ABSTRACT The aberrant c-Met activation has been implicated in a variety of human cancers for its critical role in tumor growth, metastasis and tumor angiogenesis. Thus, c-Met axis presents as an attractive therapeutic target. Notably, most of these c-Met inhibitors currently being evaluated in clinical trials lack selectivity and target multiple kinases, often accounting for the undesirable toxicities. Here we described Simm530 as a potent and selective c-Met inhibitor. Simm530 demonstrated >2,000 fold selectivity for c-Met compared with other 282 kinases, making it one of the most selective c-Met inhibitors described to date. This inhibitor significantly blocked c-Met signaling pathways regardless of mechanistic complexity implicated in c-Met activation. As a result, Simm530 led to substantial inhibition of c-Met-promoted cell proliferation, migration, invasion, ECM degradation, cell scattering and invasive growth. In addition, Simm530 inhibited primary human umbilical vascular endothelial cell (HUVEC) proliferation, decreased intratumoral CD31 expression and plasma pro-angiogenic factor interleukin-8 secretion, suggesting its significant anti-angiogenic properties. Simm530 resulted in dose-dependent inhibition of c-Met phosphorylation and tumor growth in c-Met-driven lung and gastric cancer xenografts. And, the inhibitor is well tolerated even at doses that achieve complete tumor regression. Together, Simm530 is a potent and highly selective c-Met kinase inhibitor that may have promising therapeutic potential in c-Met-driven cancer treatment.