新型针对 C797S 突变的 EGFR PROTACs 的设计、合成与生物学评价。
Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation.
机构信息
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
出版信息
J Med Chem. 2024 May 9;67(9):7283-7300. doi: 10.1021/acs.jmedchem.4c00107. Epub 2024 Apr 27.
The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application of Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy to overcome drug resistance. In this study, some novel PROTACs targeting C797S mutation were designed and synthesized based on a new EGFR inhibitor and displayed a potent degradation effect in H1975-TM cells harboring EGFR. The representative compound exhibited a DC of 10.2 nM against EGFR and an IC of 10.3 nM against H1975-TM. Furthermore, also showed potent degradation activity against various main EGFR mutants, including EGFR. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, inhibited tumor growth in the H1975-TM xenograft tumor model effectively and safely. This study identifies a novel and potent EGFR PROTAC to overcome Osimertinib resistance mediated by C797S mutation.
表皮生长因子受体（EGFR）三级 C797S 突变是对奥希替尼产生耐药的重要原因，严重阻碍了奥希替尼的临床应用。针对 EGFR 突变体的蛋白水解靶向嵌合体（PROTACs）的开发提供了克服耐药性的有前途的策略。在这项研究中，基于新型 EGFR 抑制剂设计并合成了一些针对 C797S 突变的新型 PROTACs，并在携带 EGFR 的 H1975-TM 细胞中显示出强大的降解作用。代表性化合物 对 EGFR 的 DC 为 10.2 nM，对 H1975-TM 的 IC 为 10.3 nM。此外， 还对包括 EGFR 在内的各种主要 EGFR 突变体表现出强大的降解活性。机制研究表明，蛋白质降解是通过泛素-蛋白酶体系统实现的。最后， 在 H1975-TM 异种移植肿瘤模型中有效且安全地抑制了肿瘤生长。这项研究确定了一种新型有效的 EGFR PROTAC，可克服由 C797S 突变介导的奥希替尼耐药性。
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