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第三代II型宏循环TRK抑制剂的基于结构的优化,具有针对溶剂前线,xDFG和守门员突变的改善活性

Zuqin Wang¹, Jie Wang¹, Yongjin Wang¹

¹International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.

Journal of medicinal chemistry

|September 7, 2023

概括

新的宏循环化合物,包括10g化合物,显示出对抗耐受性热氨酸受体激酶 (TRK) 突变的强烈抑制. 这提供了一个有前途的策略,以克服针对性癌症治疗的获得性耐药性.

科学领域:

在瘤学瘤学.
药用化学医学化学
分子生物学分子生物学

背景情况:

获得对特罗波米奥辛受体激酶 (TRK) 抑制剂的耐药性,如拉罗特雷克提尼布和恩特雷克提尼布是由突变 (SF,守门人,xDFG) 驱动的.
现有的疗法缺乏有效的治疗方法来克服这些特定的TRK突变,从而造成未满足的临床需求.

研究的目的:

设计和合成新型II型TRK抑制剂,以对抗临床相关的TRK突变.
确定一种有效抗 TRK 突变的化合物,使其对当前疗法产生抗性.

主要方法:

一系列针对TRK的宏循环化合物的合成.
在体外生化测试以确定与野生类型和突变TRK激酶对抗的IC50值.
用各种TRK突变感染的Ba/F3细胞进行细胞增殖试验.
使用异种移植模型进行的体内疗效研究.

主要成果:

化合物10g证明对野生型TRKA/C和关键耐药突变 (TRKA^G595R,TRKA^G667C,TRKA^F589L) 具有低纳米IC50值的强有力的抑制.
化合物10g在378个激酶中表现出强烈的选择性.
它有效地抑制了携带单个TRK突变 (SF,GK,xDFG) 的Ba/F3细胞的增殖.
在BaF3-CD74-NTRK1^G595R和BaF3-CD74-NTRK1^G667C异种移植模型中观察到显著的抗瘤疗效.

结论:

化合物10g代表了一个有前途的化合物,用于开发新的抗癌药物.
这种宏循环抑制剂有效地向导致对现有疗法产生耐药性的TRK突变.
这些发现支持10g在泛癌治疗策略中的潜力.

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