Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC
Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC
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基于结构的设计和合成 2,4-二氨基嘧啶作为 NSCLC EGFR L858R/T790M 选择性抑制剂
DOI：
10.1016/j.ejmech.2017.08.061
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发表时间：
2017-11-10
影响因子：
6.7
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Lingfeng;Fu, Weitao;Liang, Guang
突变的表皮生长因子受体（EGFR）是非小细胞肺癌（NSCLC）的主要驱动因素。EGFR（T790m）继发突变已成为临床获得性吉非替尼和厄洛替尼耐药的主要原因。在此，我们提出了一种基于结构的设计方法，以增加以前报道的可逆EGFR抑制剂7的效力和选择性，在激酶和细胞水平。通过三步构效关系探索，得到了具有独特化学结构和结合模式的化合物19 e和19 h。在人NSCLC异种移植模型中，19 e和19 h表现出剂量依赖性肿瘤生长抑制，无毒性。这些选择性抑制剂是EGFR（T790M）驱动的NSCLC的有希望的候选药物。(C)2017年Elsevier Masson SAS。All rights reserved.
Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFR(T790m) 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(T790M)-driven NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.