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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Structure-Based Discovery of Active Pan-KRas Inhibitors Targeting G12D Mutants by Enhanced Sampling Simulations
1School of Biomedical Engineering, Guangdong Medical University, Dongguan 523808, China.
Abstract:
Ras is a node protein in the classic tumor signaling pathway known as RAS-RAF-MEK. Mutations in Ras are reported to occur in approximately 19% of human cancers. Among them, the G12D mutation is one of the most prevalent mutations found in Ras. In this study, we performed replica-exchange molecular dynamics (REMD) simulations on the KRas G12D mutant, revealing that its conformational space is remarkably different from that of wild-type KRas, particularly in State 1. Based on two specific conformations of the KRas G12D mutant, we screened an in-house molecular library. Two compounds, designated SS-3091 and SS-30125, were experimentally verified to have the strong inhibitory effects. MD simulations starting from the docked complexes revealed that SS-3091 and SS-30125 bind to the interaction interfaces of KRas and ARaf, destabilizing the ARaf·KRas complex. The anticancer activities of SS-3091 and SS-30125 have been validated against the KRas G12D, G12C, G12V, and G12S mutants in various cancer cells. All findings underscore the potential of SS-3091 and SS-30125 as very promising active pan-KRas inhibitors.
Insights
Researchers identified novel compounds SS-3091 and SS-30125 that inhibit the KRas G12D mutant. These pan-KRas inhibitors show promise for treating various cancers driven by Ras mutations.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Ras proteins are key regulators of cellular signaling pathways.
- Mutations in Ras, particularly KRas G12D, are prevalent in human cancers.
- The RAS-RAF-MEK pathway is a critical target for cancer therapy.
Purpose of the Study:
- To investigate the conformational landscape of the KRas G12D mutant.
- To identify novel inhibitors targeting KRas G12D.
- To evaluate the therapeutic potential of identified inhibitors against various Ras mutations.
Main Methods:
- Replica-exchange molecular dynamics (REMD) simulations of KRas G12D.
- Molecular library screening based on specific KRas G12D conformations.
- Molecular docking and molecular dynamics (MD) simulations of inhibitor-protein complexes.
- In vitro validation of anticancer activity against multiple KRas mutants.
Main Results:
- KRas G12D exhibits a distinct conformational space compared to wild-type KRas.
- Two compounds, SS-3091 and SS-30125, demonstrated significant inhibitory effects.
- SS-3091 and SS-30125 destabilize the KRas-ARaf complex by binding to their interaction interfaces.
- These compounds showed validated anticancer activity across KRas G12D, G12C, G12V, and G12S mutants.
Conclusions:
- SS-3091 and SS-30125 are potent inhibitors of KRas G12D and other Ras mutants.
- These compounds represent promising therapeutic candidates for a broad spectrum of KRas-driven cancers.
- The findings highlight the potential of targeting specific KRas conformations for drug discovery.
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