Small-molecule degraders for oncogenic KRAS^G12C and pan-KRAS mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is a key oncogene frequently mutated in various cancers.
• Targeting KRAS G12C mutations with covalent inhibitors like sotorasib shows limited efficacy due to acquired resistance.
• Targeted protein degradation offers an alternative therapeutic strategy, but often requires large molecules.

Purpose of the Study:

• To develop a small-molecule degrader for KRAS G12C.
• To investigate the mechanism of action and efficacy of the novel degrader.
• To explore the potential for developing pan-KRAS degraders.

Main Methods:

• Design of DJX-A-KM by incorporating an acrylamide warhead into the MRTX849 scaffold.
• Assessment of KRAS G12C degradation in vitro and in vivo.
• Mechanistic studies involving ubiquitin-proteasome system and E3 ligase interaction.
• Antiproliferation assays in KRAS G12C-mutant cancer models.

Main Results:

• DJX-A-KM induces potent and sustained degradation of KRAS G12C.
• Degradation is mediated by the ubiquitin-proteasome system via covalent engagement with FBXO28.
• DJX-A-KM exhibits potent antiproliferative effects in KRAS G12C-mutant cancer models.
• The strategy shows potential for developing pan-KRAS degraders.

Conclusions:

• DJX-A-KM is a novel small-molecule KRAS G12C degrader with therapeutic potential.
• The study highlights FBXO28 as an E3 ligase for targeted protein degradation.
• This approach provides a blueprint for developing new degraders against KRAS mutations and other targets.