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Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs

10 April 2020, Version 1
Working Paper
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

KRas
PROTAC
Protein Degradation
VHL
E3 Ligase

Supplementary materials

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KRAS Supplemental Figures Final v2
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Supporting Information
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Now Published

Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs [opens in a new tab]
Michael J. Bond, Ling Chu, Dhanusha A. Nalawansha, Ke Li, Craig M. Crews journal article
ACS Central Science , Volume 6, Issue 8
Online publication date: Jul 08, 2020

Version History

Apr 10, 2020 Version 1

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv.12091176.v1
D O I: 10.26434/chemrxiv.12091176.v1 [opens in a new tab]

Funding

NIH (R35CA197589)
NIH (F31CA232477)
NIH (5T32GM067543)
American Cancer Society Professorship

Author’s competing interest statement

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

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