Sogabe Satoshi, Kawakita Youichi, Igaki Shigeru, Iwata Hidehisa, Miki Hiroshi, Cary Douglas R, Takagi Terufumi, Takagi Shinji, Ohta Yoshikazu, Ishikawa Tomoyasu
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
ACS Med Chem Lett. 2012 Dec 18;4(2):201-5. doi: 10.1021/ml300327z. eCollection 2013 Feb 14.
The epidermal growth factor receptor (EGFR) family plays a critical role in vital cellular processes and in various cancers. Known EGFR inhibitors exhibit distinct antitumor responses against the various EGFR mutants associated with nonsmall-cell lung cancer. The L858R mutation enhances clinical sensitivity to gefitinib and erlotinib as compared with wild type and reduces the relative sensitivity to lapatinib. In contrast, the T790M mutation confers drug resistance to gefitinib and erlotinib. We determined crystal structures of the wild-type and T790M/L858R double mutant EGFR kinases with reversible and irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285 and neratinib. In these structures, M790 adopts distinct conformations to accommodate different inhibitors, whereas R858 allows conformational variations of the activation loop. These results provide structural insights for understanding the structure-activity relationships that should contribute to the development of potent inhibitors against drug-sensitive or -resistant EGFR mutations.
表皮生长因子受体（EGFR）家族在重要的细胞过程和多种癌症中发挥着关键作用。已知的EGFR抑制剂对与非小细胞肺癌相关的各种EGFR突变表现出不同的抗肿瘤反应。与野生型相比，L858R突变增强了对吉非替尼和厄洛替尼的临床敏感性，并降低了对拉帕替尼的相对敏感性。相反，T790M突变赋予了对吉非替尼和厄洛替尼的耐药性。我们基于TAK - 285和neratinib的类似物，确定了野生型以及T790M/L858R双突变EGFR激酶与可逆和不可逆吡咯并[3,2 - d]嘧啶抑制剂的晶体结构。在这些结构中，M790采用不同的构象来容纳不同的抑制剂，而R858允许激活环的构象变化。这些结果为理解结构 - 活性关系提供了结构见解，这应有助于开发针对药物敏感或耐药EGFR突变的有效抑制剂。
