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Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs

Michael J Bond1, Ling Chu2, Dhanusha A Nalawansha2

  • 1Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States.

ACS Central Science
|September 3, 2020
PubMed

Insights

Researchers developed LC-2, a novel Proteolysis-Targeting Chimera (PROTAC), to degrade the KRAS G12C mutant protein. This new approach offers a promising strategy for targeting KRAS-driven cancers by reducing oncogenic KRAS levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS mutations are prevalent in human cancers, historically posing a significant therapeutic challenge.
  • Recent advances include covalent inhibitors for KRAS G12C, but alternative strategies are needed.
  • Proteolysis-Targeting Chimeras (PROTACs) offer a novel mechanism for protein degradation.

Purpose of the Study:

  • To develop and characterize the first PROTAC capable of degrading endogenous KRAS G12C.
  • To evaluate the efficacy of PROTAC-mediated KRAS G12C degradation in cancer cell lines.
  • To explore PROTACs as a complementary strategy to small molecule inhibitors for KRAS-driven cancers.

Main Methods:

  • Design and synthesis of a novel PROTAC, LC-2, incorporating a KRAS G12C-specific covalent warhead (MRTX849).
  • Utilizing VHL as the E3 ligase for targeted protein degradation.
  • Assessing KRAS G12C degradation and downstream signaling (MAPK pathway) in cancer cell lines (homozygous and heterozygous).

Main Results:

  • LC-2 successfully induced rapid and sustained degradation of endogenous KRAS G12C.
  • Degradation was observed in both homozygous and heterozygous KRAS G12C cancer cell lines.
  • Suppression of MAPK signaling was achieved following LC-2 treatment.

Conclusions:

  • PROTAC-mediated degradation is a viable strategy for targeting oncogenic KRAS G12C.
  • LC-2 represents a first-in-class PROTAC for KRAS G12C degradation.
  • This approach has the potential to overcome limitations of traditional KRAS inhibitors.

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