Efficient targeted oncogenic KRASG12C 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 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.

Automated summary

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.