Abstract 3612: A novel and selective c-Met inhibitor against subcutaneous xenograft and othotopic brain tumor models

Abstract

Abstract HM5016504 is a novel, highly potent and selective c-Met inhibitor under development by HMPL. In preclinical studies, it demonstrated strong in vitro activity against c-Met and its downstream signaling targets, thus blocking the related cellular functions, including proliferation, migration, invasion, scattering and the secretion of VEGF that plays a pivotal role in tumor angiogenesis. The cross-talk between c-Met and EGFR was investigated, and their contribution to downstream signaling cascade was identified in certain tumor cell lines with dysregulation of both c-Met and EGFR. HM5016504 could effectively inhibit the in vivo growth of a number of human tumor xenografts. Particularly, the tumor cells or xengorafts with high fold of c-Met gene amplification showed high sensitivity to HM5016504, such as gastric cancer SNU-5, Hs746T and lung cancer H1993 and EBC-1 cells or their respective xenografts. The compound not only showed activity in subcutaneous xenograft models, but also demonstrated efficacy in an orthotopic brain tumor model induced by U87MG, indicating it could pass blood brain barrier. In vitro and in vivo activities of HM5016504 were found to be closely correlated with the c-Met expression level and activation status. In addition, HM5016504 exhibited a reasonable pharmacokinetic profile and safety window based on the toxicology study results in rats, dogs, and monkeys. The pre-clinical study results suggest that HM5016504 could be a promising c-Met targeting anti-cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2011-3612