Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Ras proteins, particularly KRAS, are frequently mutated in various cancers, acting as dominant oncogenes.
• Mutant KRAS, specifically the G12C variant, presents a significant therapeutic target in oncology.
• Previous development of SML-8-73-1, an irreversible inhibitor of G12C RAS, highlighted the potential of covalent inhibition.

Purpose of the Study:

• To explore structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1.
• To discover novel covalent G12C KRAS inhibitors with improved drug-like properties.
• To lay the groundwork for developing prodrugs to enhance cellular uptake of G12C KRAS inhibitors.

Main Methods:

• Synthesis and characterization of novel difluoromethylene bisphosphonate analogues.
• Evaluation of covalent inhibitory efficiency against G12C KRAS.
• Structure-activity relationship (SAR) studies to guide analogue design.
• Crystallographic analysis to understand molecular recognition at the RAS diphosphate binding site.

Main Results:

• Discovery of difluoromethylene bisphosphonate analogues, exemplified by compound 11.
• These analogues exhibit reduced efficiency as direct covalent G12C KRAS inhibitors compared to SML-8-73-1.
• The novel analogues successfully mitigate the hydrolytic instability associated with the diphosphate moiety of SML-8-73-1.
• Findings provide a foundation for developing prodrug strategies to improve cellular delivery.

Conclusions:

• Difluoromethylene bisphosphonate analogues represent a promising scaffold for developing stable G12C KRAS inhibitors.
• Addressing hydrolytic instability is crucial for advancing covalent KRAS inhibitors.
• The molecular recognition in the RAS diphosphate region is key for designing effective nucleotide-competitive inhibitors.