Pharmacologic characterization of CT-711, a novel dual inhibitor of ALK and c-Met

American Journal of Cancer Research

Lei Wang¹ 

[1] Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

关键词: CT-711;    ALK;    c-Met;    crizotinib;    antitumor activity;    pharmacokinetics;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Anaplastic lymphoma kinase (ALK) is a validated molecular target for patients harboring ALK rearrangement, which triggers the development of ALK inhibitors. However, the activation of mesenchymal-epithelial transition factor (c-Met) has emerged as a common cause of acquired resistance induced by selective ALK inhibitors. Herein, we report the first preclinical characterization of CT-711, a novel dual inhibitor of ALK and c-Met. CT-711 demonstrates potent inhibitory activity against ALK kinase activity. Moreover, CT-711 profoundly inhibits ALK signal transduction and thereby induces G1 phase arrest and apoptosis, and results in remarkable anti-proliferative activity against ALK-driven cancer cells. Furthermore, CT-711 effectively inhibits c-Met kinase activity and potently overcomes the resistance mediated by c-Met activation. When orally administered to nude mice bearing xenografts, CT-711 exhibits favorable pharmacokinetic properties and robust antitumor activity. It is noteworthy that CT-711 is superior to crizotinib, the first-in-class ALK inhibitor, in the treatment of ALK-driven cancers in various models. The results of the current study provide a solid foundation for the clinical investigation of CT-711 in patients with tumors harboring ALK rearrangement.

【 授权许可】

CC BY-NC