基于蛋白激酶ALK与非经典底物蛋白-蛋白相互作用及基因突变协同耐药机制的新型ALK抑制剂研究

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers through various gene alterations, among which the fusion gene EML4-ALK was identified specifically existing in lung cancers and has emerged as a novel and promising ‘personalized’ molecular target of cancers. Although the early FDA-approved ALK inhibitor crizotinib achieved significant responses, the majority of patients relapse during the first year of treatment due to the development of resistance. Therefore, deciphering and overcoming the underling mechanism of resistance has become a bottleneck for the development of new generation of ALK inhibitors. In this project, we propose a joint mechanism, not only based on gene mutations - the classic resistance mechanism of kinase inhibitors, and also on the non-kinase activity involving the protein-protein interaction (PPI) between ALK kinase and its atypical substrates. In this regard, we will first design and synthesize new compounds based on ALK mutants, especially the gatekeeper mutation L1196M, and then use these compounds as tools to investigate resistance-relevant atypical substrates, their interaction with ALK (PPI), and the correlation between mutant ALK conformations and PPI. The results will not only assist to establish the joint mechanism of resistance, identify new substrates and corresponding PPI with ALK kinase, but also to open a new avenue for discovery of our own new ALK inhibitors overcoming both the PPI and kinase mutations.

酪氨酸激酶ALK与棘皮动物微管蛋白样-4形成的融合蛋白EML4-ALK是近年来新发现的癌变驱动基因,其靶向性抑制剂已成为抗肿瘤药物研究的前沿热点。全面阐释已发现抑制剂的耐药机制并进行针对性的药物设计是目前ALK抑制剂研究面临的瓶颈和亟需解决的关键科学问题。本项目将基于基因突变这一经典耐药机制，结合ALK与非经典底物间蛋白-蛋白相互作用（PPI）介导的非酶活功能，建立ALK抑制剂协同耐药机制。首先通过基因突变寻找对突变型ALK，尤其是‘卡口残基’突变敏感的化合物，以此为工具研究与耐药性相关的ALK非经典底物、二者间蛋白-蛋白相互作用及其调控的非酶活功能，从更深更广层面探索ALK抑制剂的耐药机制，为进一步开展针对协同耐药机制的合理药物设计、发现既能抑ALK基因突变又能抑制ALK与非经典底物间的PPI的新一代抑制剂，并最终发展机制新颖成药性好的具有自主知识产权的抗肿瘤新药奠定基础。

酪氨酸激酶ALK是一个重要的分子靶向抗肿瘤药物靶标，目前国际上已有5个抑制剂上市，对非小细胞肺癌具有优异的治疗效果，但我国还没有自主研发的ALK抑制剂新药。本项目以第一代ALK靶向抑制剂的耐药为目标，一方面通过靶向ALK与伴侣蛋白Hsp90间的相互作用，尤其是参与相互作用的Hsp90中间结构域进行药物设计；另一方面，直接针对ALK耐药突变进行多靶点药物设计。通过系统药物评价及体内外活性测试，获得靶向Hsp90中间区域选择性抑制剂，可变构调控Hsp90的N端活性，并通过作用与底物蛋白的相互作用，实现对底物蛋白的调控，在ALK抑制剂基础上，发现多靶点激酶抑制剂盐酸希美替尼，对肾癌、食管癌、胆管癌、胃癌等具有显著抗肿瘤活性，作为1.1类候选新药完成了系统的临床前研究，并获得临床试验批件，目前正在开展临床I期试验。同时，本项目期间，相关成果发表标注本基金的SCI论文48篇，申请中国发明专利12篇，包括2篇PCT国际专利。

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