School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China; Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Eur J Med Chem. 2017 Nov 10;140:510-527. doi: 10.1016/j.ejmech.2017.08.061. Epub 2017 Sep 20.
Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFR secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three-step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFR-driven NSCLC.
表皮生长因子受体（EGFR）突变是导致非小细胞肺癌（NSCLC）的主要驱动因素。EGFR 继发突变已成为吉非替尼和厄洛替尼获得性耐药的主要原因。在此，我们提出了一种基于结构的设计方法，旨在提高先前报道的可逆 EGFR 抑制剂 7 的效力和选择性，分别在激酶和细胞水平上。三步骤的构效关系探索得到了有前途的化合物 19e 和 19h，它们具有独特的化学结构和结合模式，与其他第三代酪氨酸激酶抑制剂不同。在人 NSCLC 异种移植模型中，19e 和 19h 表现出剂量依赖性的肿瘤生长抑制作用，且无毒性。这些选择性抑制剂是针对 EGFR 驱动的 NSCLC 的有前途的药物候选物。
