Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-27 , DOI: 10.1021/acs.jmedchem.4c00107
Yasheng Zhu _{1,

2,

3} , Xiuquan Ye _{1,

4} , Yuxing Wu _{1,

4} , Hao Shen _{1,

2,

3} , Zeyu Cai _{1,

2,

3} , Fei Xia _{1,

2,

3} , Wenjian Min _{1,

2,

3} , Yi Hou _{1,

2,

3} , Liping Wang _{1,

2,

3} , Xiao Wang _{1,

2,

3} , Yibei Xiao _{1,

4,

5} , Peng Yang _{1,

2,

3}

Affiliation

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^{L858R/T790M/C797S}. The representative compound C6 exhibited a DC₅₀ of 10.2 nM against EGFR^{L858R/T790M/C797S} and an IC₅₀ of 10.3 nM against H1975-TM. Furthermore, C6 also showed potent degradation activity against various main EGFR mutants, including EGFR^{Del19/T790M/C797S}. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin–proteasome system. Finally, C6 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.

中文翻译：

针对 C797S 突变的新型 EGFR PROTAC 的设计、合成和生物学评价

表皮生长因子受体（EGFR）三级C797S突变是奥希替尼耐药的重要原因，严重阻碍了奥希替尼的临床应用。开发针对 EGFR 突变体的蛋白水解靶向嵌合体 (PROTAC) 可以提供一种有前景的克服耐药性的策略。在本研究中，基于新型EGFR抑制剂，设计并合成了一些针对C797S突变的新型PROTAC，并在含有EGFR ^{L858R/T790M/C797S}的H1975-TM细胞中显示出有效的降解作用。代表性化合物C6针对EGFR ^{L858R/T790M/C797S}表现出10.2nM的DC ₅₀ ，针对H1975-TM表现出10.3nM的IC ₅₀ 。此外， C6还对各种主要 EGFR 突变体（包括 EGFR ^{Del19/T790M/C797S）}表现出有效的降解活性。机理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， C6有效且安全地抑制H1975-TM异种移植肿瘤模型中的肿瘤生长。这项研究确定了一种新型有效的 EGFR PROTAC，可以克服 C797S 突变介导的奥希替尼耐药性。

更新日期：2024-04-27

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