Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Mei Zeng, Yuan Xiong, Nozhat Safaee, Radosław P. Nowak, Katherine A. Donovan, Christine J. Yuan, Behnam Nabet, Thomas W. Gero, Frederic Feru, Lianbo Li, Sudershan Gondi, Lincoln J. Ombelets, Chunshan Quan, Pasi A. Jänne, Milka Kostic, David A. Scott, Kenneth D. Westover, Eric S. Fischer, Nathanael S. Gray

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRASG12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/KRASG12C dimerization, and degraded GFP-KRASG12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRASG12C. KRASG12C is an oncoprotein of high interest for drug development. Zeng et al. investigate targeting KRASG12C for degradation using small-molecule degraders (PROTACs) and document challenges and opportunities in this area.

Original languageEnglish (US)
Pages (from-to)19-31.e6
JournalCell Chemical Biology
Volume27
Issue number1
DOIs
StatePublished - Jan 16 2020

Keywords

  • CRBN
  • KRAS
  • PROTAC
  • caner
  • degrader
  • targeted protein degradation
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Zeng, M., Xiong, Y., Safaee, N., Nowak, R. P., Donovan, K. A., Yuan, C. J., Nabet, B., Gero, T. W., Feru, F., Li, L., Gondi, S., Ombelets, L. J., Quan, C., Jänne, P. A., Kostic, M., Scott, D. A., Westover, K. D., Fischer, E. S., & Gray, N. S. (2020). Exploring Targeted Degradation Strategy for Oncogenic KRASG12C Cell Chemical Biology, 27(1), 19-31.e6. https://doi.org/10.1016/j.chembiol.2019.12.006