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Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Mei Zeng1, Yuan Xiong1, Nozhat Safaee1

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Cell Chemical Biology
|December 30, 2019
PubMed

Insights

Researchers developed PROTACs to target KRASG12C, a common cancer mutation. While the lead PROTAC degraded a KRASG12C-GFP fusion protein, it failed to degrade endogenous KRASG12C in cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS is a frequently mutated oncogene in pancreatic, colorectal, and lung cancers.
  • Targeting KRASG12C mutations with covalent inhibitors is a promising therapeutic strategy.
  • Developing effective KRASG12C degraders remains a significant challenge in cancer therapy.

Purpose of the Study:

  • To design and evaluate C12-directed Proteolysis Targeting Chimeras (PROTACs) for KRASG12C degradation.
  • To identify a lead PROTAC compound with potent KRASG12C-targeting capabilities.
  • To investigate the efficacy and limitations of PROTACs in degrading endogenous KRASG12C.

Main Methods:

  • A library of C12-directed covalent PROTACs was synthesized.
  • Lead compound evaluation involved in vitro binding assays and cellular assays.
  • CRBN engagement, KRASG12C binding, dimerization, and degradation of GFP-KRASG12C were assessed.
  • Degradation of endogenous KRASG12C in cancer cell lines was evaluated.

Main Results:

  • The lead PROTAC engaged CRBN, bound KRASG12C, and induced CRBN/KRASG12C dimerization.
  • The PROTAC successfully degraded GFP-KRASG12C in reporter cells dependent on CRBN.
  • However, the PROTAC failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells.

Conclusions:

  • The lead PROTAC's inability to effectively poly-ubiquitinate endogenous KRASG12C underlies its lack of activity.
  • Challenges in achieving targeted KRASG12C degradation were identified.
  • Potential solutions for efficient degradation of endogenous KRASG12C were proposed.
Keywords:
CRBNKRAS(G12C)PROTACcanerdegradertargeted protein degradationubiquitination

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