ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
0/0

Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs

preprint
submitted on 07.04.2020 and posted on 10.04.2020 by Michael J. Bond, Ling Chu, Dhanusha A. Nalawansha, Ke Li, Craig Crews

We report the development of LC-2, the first PROTAC capable of degrading endogenous KRASG12C. LC-2 covalently binds KRASG12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRASG12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRASG12C cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.

Funding

NIH (R35CA197589)

NIH (F31CA232477)

NIH (5T32GM067543)

American Cancer Society Professorship

History

Email Address of Submitting Author

craig.crews@yale.edu

Institution

Yale University

Country

USA

ORCID For Submitting Author

0000-0002-8456-2005

Declaration of Conflict of Interest

C.M.C is founder, shareholder, and consultant to Arvinas, Inc., which supports research in his laboratory.

Exports

Read the published paper

in ACS Central Science

Logo branding

Exports