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Updated: Jul 13, 2025
Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual
Patricia Gomez-Gutierrez1,2, Jaime Rubio-Martinez3, Juan J Perez1
1Department of Chemical Engineering. ETSEIB, Universitat Politecnica de Catalunya, Av. Diagonal, 647, Barcelona 08028, Spain.
Abstract:
Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1-P8) in K-Ras, four of which (P1-P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 μM.
Insights
Researchers identified novel allosteric K-Ras inhibitors by computationally screening for compounds targeting the P4 pocket. These potential cancer therapeutics show significant cell proliferation inhibition, offering new hope for targeted cancer treatment.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Mutant Ras proteins are key drivers in numerous human cancers.
- Ras proteins were historically considered undruggable due to high substrate affinity.
- Allosteric modulators targeting cryptic pockets offer a viable therapeutic strategy.
Purpose of the Study:
- To computationally characterize eight potential allosteric pockets in K-Ras (P1-P8).
- To perform virtual screening to identify novel K-Ras P4 allosteric site binders.
- To discover peptidomimetic compounds targeting the SOS αI helix interaction site.
Main Methods:
- Utilized computational methods to analyze K-Ras allosteric pockets.
- Conducted virtual screening to identify potential drug candidates.
- Assessed compound efficacy using cell proliferation assays.
Main Results:
- Characterized eight prospective allosteric pockets in K-Ras, including four previously known sites.
- Identified five hit compounds that bind to the K-Ras P4 allosteric site.
- Discovered compounds demonstrating over 30% inhibition in cell proliferation assays at 50 μM.
Conclusions:
- The identified compounds are promising K-Ras P4 allosteric site binders.
- These novel inhibitors exhibit significant anti-proliferative activity.
- The findings support the development of new targeted cancer therapies for Ras-driven tumors.
