EGFR-PI3K-Akt-mTOR 信号通路的异常激活或突变与多种人类癌症有关，尤其是非小细胞肺癌 (NSCLC)。因此，EGFR 和 PI3K 的双重抑制已被研究为解决因使用酪氨酸激酶抑制剂而产生的获得性耐药性的有前途的策略。采用第三代EGFR抑制剂奥穆替尼和PI3Kα选择性抑制剂TAK-117的药效团杂交合成了一系列EGFR/PI3Kα双抑制剂。最佳化合物 30k 显示出有效的激酶抑制活性，针对 EGFRL858R/T790M 和 PI3Kα 的 IC50 值分别为 3.6 和 30.0 nM。化合物 30k 在 NCI-H1975 细胞中表现出显着的抗增殖作用，且选择性高于 olmutinib。还阐明了化合物 30k 的潜在抗肿瘤机制、分子结合模式和体外代谢稳定性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.Copyright © 2024 Elsevier Inc. All rights reserved.