Efficient targeted oncogenic KRAS(G12C) degradation via first reversible-covalent PROTAC

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...

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Bibliographic Details
Published inEuropean journal of medicinal chemistry Vol. 230
Main Authors Yang, Fang, Wen, Yalei, Wang, Chaofan, Zhou, Yuee, Zhou, Yang, Zhang, Zhi-Min, Liu, Tongzheng, Lu, Xiaoyun
Format Journal Article
LanguageEnglish
Published ISSY-LES-MOULINEAUX Elsevier 15.02.2022
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Reversible-covalent inhibitors
PROTAC
PROTEIN-DEGRADATION
KRAS
INHIBITORS
Anticancer
KRAS(G12C)
AMG 510
CANCER
DISCOVERY
Warheads
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Summary: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.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.114088