D'Angelo Noel D, Bellon Steven F, Booker Shon K, Cheng Yuan, Coxon Angela, Dominguez Celia, Fellows Ingrid, Hoffman Douglas, Hungate Randall, Kaplan-Lefko Paula, Lee Matthew R, Li Chun, Liu Longbin, Rainbeau Elizabeth, Reider Paul J, Rex Karen, Siegmund Aaron, Sun Yaxiong, Tasker Andrew S, Xi Ning, Xu Shimin, Yang Yajing, Zhang Yihong, Burgess Teresa L, Dussault Isabelle, Kim Tae-Seong
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA.
J Med Chem. 2008 Sep 25;51(18):5766-79. doi: 10.1021/jm8006189.
c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.
c-Met是一种受体酪氨酸激酶，在多个细胞过程中发挥关键作用，但也发现在不同的人类癌症中存在过表达和突变。因此，靶向这种酶已成为药物研发中一个热门的研究领域。我们的研究始于新型嘧啶酮7的设计与合成，发现它是一种有效的c-Met抑制剂。随后的构效关系（SAR）研究确定22是一种更有效的类似物，而与c-Met结合的7的X射线晶体结构揭示了一种意想不到的结合构象。后一发现促成了一个新系列的开发，该系列化合物在体外和体内都比22更有效，并且与c-Met呈现出不同的结合构象。新型c-Met抑制剂已被设计、开发出来，并发现它们在体外和体内都具有效力。
