Identification of Noncovalent Small-Molecules from Virtual Screening Toward the Development of Potential KRAS...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Kirsten rat sarcoma (KRAS) is a key oncoprotein implicated in approximately 20% of human cancers.
• Current FDA-approved treatments for KRAS (G12C)-driven non-small cell lung cancer are limited to two covalent drugs.
• The development of noncovalent KRAS inhibitors is crucial due to resistance to allele-specific drugs and limitations of covalent inhibitors for non-G12C mutations.

Purpose of the Study:

• To identify novel small molecules with high affinity for multiple KRAS mutants.
• To explore new therapeutic strategies for KRAS-driven cancers beyond existing covalent inhibitors.
• To discover potential starting points for developing allele-specific or pan-KRAS inhibitors.

Main Methods:

• Virtual screening of a tailored ligand library against multiple KRAS mutants.
• In vitro binding assays to determine inhibitor affinity.
• Cell proliferation assays in pancreatic cancer cell lines with various KRAS mutations (G12D, G12V, G12C).

Main Results:

• Identified small molecules exhibiting high affinity (single-digit nM) binding to KRAS.
• Demonstrated sub-to-low micromolar inhibitory activity in pancreatic cancer cell lines with G12D, G12V, or G12C KRAS mutations.
• Predicted binding to the KRAS p2 (switch II) pocket with unique scaffolds.

Conclusions:

• The identified small molecules represent promising leads for developing novel noncovalent KRAS inhibitors.
• These compounds may overcome limitations of current covalent therapies and address resistance mechanisms.
• The unique scaffolds offer a new avenue for developing targeted therapies for a broad range of KRAS-mutated cancers.