American Journal of Cancer Research | |
Pharmacologic characterization of CT-711, a novel dual inhibitor of ALK and c-Met | |
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
【 预 览 】
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