Exploring Targeted Degradation Strategy for Oncogenic KRAS^G12C

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is a frequently mutated oncogene in pancreatic, colorectal, and lung cancers.
• Targeting KRAS^G12C mutations with covalent inhibitors is a promising therapeutic strategy.
• Developing effective KRAS^G12C degraders remains a significant challenge in cancer therapy.

Purpose of the Study:

• To design and evaluate C12-directed Proteolysis Targeting Chimeras (PROTACs) for KRAS^G12C degradation.
• To identify a lead PROTAC compound with potent KRAS^G12C-targeting capabilities.
• To investigate the efficacy and limitations of PROTACs in degrading endogenous KRAS^G12C.

Main Methods:

• A library of C12-directed covalent PROTACs was synthesized.
• Lead compound evaluation involved in vitro binding assays and cellular assays.
• CRBN engagement, KRAS^G12C binding, dimerization, and degradation of GFP-KRAS^G12C were assessed.
• Degradation of endogenous KRAS^G12C in cancer cell lines was evaluated.

Main Results:

• The lead PROTAC engaged CRBN, bound KRAS^G12C, and induced CRBN/KRAS^G12C dimerization.
• The PROTAC successfully degraded GFP-KRAS^G12C in reporter cells dependent on CRBN.
• However, the PROTAC failed to degrade endogenous KRAS^G12C in pancreatic and lung cancer cells.

Conclusions:

• The lead PROTAC's inability to effectively poly-ubiquitinate endogenous KRAS^G12C underlies its lack of activity.
• Challenges in achieving targeted KRAS^G12C degradation were identified.
• Potential solutions for efficient degradation of endogenous KRAS^G12C were proposed.