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Identification of Noncovalent Small-Molecules from Virtual Screening Toward the Development of Potential KRAS
Amanuel G Addis1, Jacob Jakubec2, John Sanchez3
1Department of Physics, College of Science, Bahir Dar University, P.O. Box 79, Bahir Dar 6000, Ethiopia.
Abstract:
Kirsten rat sarcoma (KRAS) is an oncoprotein responsible for ∼ 20% of all human cancers. So far, only two covalent drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of KRAS (G12C)-driven non-small cell lung cancer. However, their reliance on a covalent bond with cysteine at position 12 limits their effectiveness for treating other cancers driven by non-G12C KRAS mutations, and the emergence of resistance against allele-specific inhibitors means that considerable effort is being directed toward developing noncovalent KRAS inhibitors. Currently, multiple noncovalent inhibitors are in various stages of clinical trials. While some of these may eventually come to fruition, none has so far been approved for market use, underscoring the need for new inhibitors. Here, we report a set of small molecules obtained from virtual screening of a physiochemically tailored ligand library against multiple KRAS mutants. Initial binding and cell proliferation experiments show that some of the predicted hits exhibit high affinity (single digit nM) binding to KRAS and sub-to-low micromolar inhibitory activity in pancreatic cancer cell lines harboring G12D, G12V, or G12C KRAS mutations. Predicted to bind to the p2 (also called switch II) pocket of KRAS, these ligands harbor unique scaffolds compared to existing drugs or leads and may serve as useful starting points for the development of allele-specific or pan-KRAS inhibitors.
Insights
New small molecules targeting Kirsten rat sarcoma (KRAS) oncoprotein show promise for treating various cancers. These noncovalent inhibitors bind KRAS with high affinity, offering potential for developing new therapies against KRAS-mutated cancers.
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.
