Collie Gavin W, Koh Cheryl M, O'Neill Daniel J, Stubbs Christopher J, Khurana Puneet, Eddershaw Alice, Snijder Arjan, Mauritzson Fredrik, Barlind Louise, Dale Ian L, Shaw Joseph, Phillips Christopher, Hennessy Edward J, Cheung Tony, Narvaez Ana J
Discovery Sciences, R&D, AstraZeneca, Cambridge, U.K.
Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
ACS Med Chem Lett. 2019 Aug 2;10(9):1322-1327. doi: 10.1021/acsmedchemlett.9b00276. eCollection 2019 Sep 12.
Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
许多cMET受体酪氨酸激酶的小分子抑制剂已在癌症治疗的临床试验中进行了评估，并且已经开始报道多种此类化合物的cMET耐药性突变。现在需要在分子水平上了解特定的cMET突变，特别是关于小分子识别方面。为此，我们在此报告最近临床观察到的赋予耐药性的D1228V cMET突变体与小分子抑制剂复合物的首个晶体结构，以及临床化合物赛沃替尼结合的野生型cMET的晶体结构，并提供支持性的细胞、生化和生物物理数据。我们的研究结果表明，D1228V改变会诱导激酶的构象变化，这可能对小分子抑制剂的设计产生影响。我们在此报告的数据增加了我们对D1228V cMET突变的分子理解，并为未来的抑制剂设计提供了见解。
