NRF2.com
Back to Research
Drug Development

A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2.

Cancer discovery

Abstract

Roy and colleagues describe VVD-065, a covalent allosteric molecular glue that binds KEAP1 at Cys151 to enhance KEAP1-CUL3 assembly, restore NRF2 ubiquitination and degradation, and selectively suppress NRF2-driven tumors by reactivating endogenous E3 ligase function. See related article by Roy et al., p. 953.

Key Findings

  • VVD-065 is a covalent allosteric molecular glue that binds KEAP1 at Cys151.
  • VVD-065 enhances KEAP1-CUL3 assembly, restoring NRF2 ubiquitination and degradation.
  • VVD-065 selectively suppresses NRF2-driven tumors by reactivating endogenous E3 ligase function.

Clinical Significance

VVD-065 represents a novel therapeutic strategy to target NRF2-driven cancers by restoring KEAP1 function, potentially improving treatment outcomes for patients with tumors exhibiting NRF2 pathway activation.

Citation

Hintzen Jordi C J, Burslem George M. A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2. Cancer discovery. 2026-May-01.

DOI: 10.1158/2159-8290.CD-26-0342