Mechanism of CH5424802 against the L1196M gatekeeper mutation of ALK

• 作 者: Mu-Yang He Qing-Chuan Zheng Qiao Xue Hong-Xing Zhang
• 机 构: StateKeyLaboratoryofTheoreticalandComputationalChemistry,InstituteofTheoreticalChemistry,JilinUniver
• 出 处: 第七届国际分子模拟与信息技术应用学术会议
• 发表日期: 2014年10期

　　Anaplastic lymphoma kinase (ALK) is a kinase that is associated with several cancers.Crizotinib is the first ALK inhibitor approved by the U.S.Food and Drug Administration (FDA) as a first-line treatment for non-small cell lung carcinoma (NSCLC).Despite the impressive initial therapeutic response, several resistant mutations against crizotinib have been detected in the treatment of NSCLC.CH5424802, a potent and selective ALK inhibitor with a unique chemical scaffold,showing antitumor activity against ALK gene mutation, inhibited the gatekeeper mutation, and blocked EML4-ALK L 1196M-driven cell growth.In the present study,the mechanism of CH5424802 against the L 1196M gatekeeper mutation of ALK was investigated using molecular dynamics simulations.The results suggest that L1196M causes the dislocation of crizotinib with ALK.In contrast, the dominating conformational changes appear at non-active areas of ALK-CH5424802 compounds.The obtained results provide a detailed explanation of binding mechanisms of Ll196M mutant with these two inhibitors and may give a vital clue for the design of new drugs to combat crizotinib resistance.