Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
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通过第一个可逆共价 PROTAC 有效靶向致癌 KRASG12C 降解
DOI：
10.1016/j.ejmech.2021.114088
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发表时间：
2022-01-07
影响因子：
6.7
通讯作者：
Lu, Xiaoyun
中科院分区：
文献类型：
--
作者：
Yang, Fang;Wen, Yalei;Lu, Xiaoyun
KRAS是最常发生突变的癌基因，在多种癌症的发生和发展中起主导作用。试图用PROTAC策略降解癌基因KRAS（G12C）被认为是对抗癌症的另一种策略。然而，不可逆的PROTACs可能会损害亚化学计量活性，从而降低效力。在此，我们报道了YF135的开发，这是第一个能够募集VHL介导的KRAS蛋白酶体降解（G12C）的可逆共价PROTAC。YF135诱导内源性KRAS（G12C）的快速持续降解，并以可逆的方式减弱H358和H23细胞中的pERK信号。(C) 2022 Elsevier Masson SAS。版权所有。
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.