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

Ye-Cheng Wang, Si-Cong Chen, Yang Cao, Yang Wu, Zhongda Shi, Celine D Wang, Michael A Norinskiy, Hasan Celik, Ziyang Zhang

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Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

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2citing papers in PubMed

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2 citing papers in PubMed.

How telomere attrition protects against cancer.Nature reviews. Genetics · 2026
Review
A safety pin against BAX.Nature chemical biology · 2026
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9 authors.

Ye-Cheng Wang *Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0003-2649-2683

Si-Cong Chen *Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0003-0764-7918

Yang Cao *Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Yang WuDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Zhongda ShiDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Celine D WangDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0001-8190-1043

Michael A NorinskiyDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Hasan CelikPines Magnetic Resonance Center, College of Chemistry, University of California, Berkeley, Berkeley, CA, USA.

Ziyang ZhangDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA. ziyang@berkeley.edu.ORCID http://orcid.org/0000-0003-0541-7211

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The RAS family of oncogenes (KRAS, HRAS, NRAS) is among the most frequently mutated genes in human cancer. Therapeutic development has largely focused on inhibitors for KRAS codon 12 mutations, while mutant-selective inhibitors for Q61 variants remain elusive. A common mechanistic feature of G12 and Q61 mutants is the reduced efficiency of GTP hydrolysis, which enriches RAS in its active, signaling-competent state. Here we report small molecules that accelerate GTP hydrolysis in KRAS-Q61 mutants as an alternative therapeutic strategy. These compounds compensate for the loss of the catalytic residue Gln61 by introducing a general base into the active site, selectively enhancing hydrolysis of KRAS-Q61X (X = H, L, K, R) mutants by up to 20-fold. In mutant cancer cell lines, these compounds reduce GTP-bound RAS levels and suppress downstream signaling. This work establishes a mechanistic foundation for small-molecule 'GTPase activators' and offers a new paradigm for targeting RAS-driven cancers.

Identifiers

PMID42587080

DOI10.1107/S0907444909052925

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