Related Experiment Video

Updated: Aug 14, 2026

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants

Ye-Cheng Wang1, Si-Cong Chen1, Yang Cao1

  • 1Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Nature Chemical Biology
|August 12, 2026
PubMed

Insights

New small molecules activate RAS GTPase activity, targeting KRAS-Q61 mutations in cancer. This approach offers a novel therapeutic strategy for RAS-driven cancers by restoring normal GTP hydrolysis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS oncogenes (KRAS, HRAS, NRAS) are frequently mutated in human cancers.
  • Current therapies primarily target KRAS codon 12 mutations, leaving KRAS Q61 variants largely untreatable.
  • RAS G12 and Q61 mutants exhibit impaired GTP hydrolysis, leading to sustained signaling.

Purpose of the Study:

  • To develop novel therapeutic strategies targeting KRAS Q61 mutations.
  • To identify small molecules that can restore GTPase activity to mutant RAS proteins.
  • To explore a new paradigm for targeting RAS-driven cancers.

Main Methods:

  • Screening for small molecules that accelerate GTP hydrolysis in KRAS-Q61 mutants.
  • Characterizing the mechanism of action of identified compounds.
  • Assessing the efficacy of compounds in mutant cancer cell lines.

Main Results:

  • Discovery of small molecules that act as GTPase activators for KRAS-Q61 mutants.
  • Compounds selectively enhance GTP hydrolysis by up to 20-fold in KRAS-Q61X mutants.
  • Treatment with these compounds reduces GTP-bound RAS levels and downstream signaling in cancer cells.

Conclusions:

  • Small-molecule GTPase activators represent a promising therapeutic strategy for KRAS-Q61 driven cancers.
  • This work provides a mechanistic basis for targeting RAS mutations via GTP hydrolysis.
  • Offers a new paradigm for developing treatments for previously intractable RAS-driven malignancies.

More Related Videos

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay13:51

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay

Published on: November 11, 2018

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

Related Concept Videos

Small GTPases - Ras and Rho01:24

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:
GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
The Ras Gene02:38

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...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Rab Proteins01:14

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...