Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

被引：56

作者：

Yang, Fang ^{[1
]}

Wen, Yalei ^{[1
]}

Wang, Chaofan ^{[1
]}

Zhou, Yuee ^{[1
]}

Zhou, Yang ^{[1
]}

Zhang, Zhi-Min ^{[1
]}

Liu, Tongzheng ^{[1
]}

Lu, Xiaoyun ^{[1
]}

机构：

[1] Jinan Univ, Coll Pharm, 601 Huangpu Ave West, Guangzhou 510632, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 230卷

基金：

中国国家自然科学基金;

关键词：

KRAS(G12C); Reversible-covalent inhibitors; PROTAC; Anticancer; Warheads; PROTEIN-DEGRADATION; AMG; 510; KRAS; INHIBITORS; DISCOVERY; CANCER;

D O I：

10.1016/j.ejmech.2021.114088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRAS(G12C) with PROTAC strategy have been considered as an alternative strategy to combate cancers. However, the irreversible PROTACs may compromise the substoichiometric activity to decrease the potency. Herein, we report the development of YF135, the first reversible-covalent PROTAC capable of recruiting VHL mediated proteasomal degradation of KRAS(G12C). YF135 induces the rapid and sustained degradation of endogenous KRAS(G12C) and attenuates pERK signaling in H358 and H23 cells in a reversible manner. (C) 2022 Elsevier Masson SAS. All rights reserved.

引用

页数：13

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