Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 230, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.114088
Keywords
KRAS(G12C); Reversible-covalent inhibitors; PROTAC; Anticancer; Warheads
Categories
Funding
- National Natural Science Foundation of China [81922062, 81874285, 81773758]
- Science and Technology Planning Project of Guangzhou City [201804010493]
- Natural Science Foundation of Guangdong Province [2019A1515011934, 2021A1515011233]
- K. C. Wong Education Foundation
- High-Performance Public Computing Service Platform of Jinan University
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This study developed a reversible-covalent PROTAC, named YF135, capable of recruiting VHL mediated proteasomal degradation of KRAS(G12C). YF135 induces rapid and sustained degradation of endogenous KRAS(G12C) and attenuates pERK signaling in cells.
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.
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