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The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...

Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

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Updated: May 12, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

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.

Juan Zeng¹, Li Li², Chi Sun²

¹School of Biomedical Engineering, Guangdong Medical University, Dongguan 523808, China.

The Journal of Physical Chemistry. B

|September 4, 2025

Summary

This summary is machine-generated.

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.

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Last Updated: May 12, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

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Published on: December 7, 2014

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

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.