What question did this study set out to answer?

The study aims to investigate the effects of VVD-065, a new molecular glue, on the control of NRF2 by KEAP1.

May 3, 2026

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

JHJordi C J HintzenUniversity of Pennsylvania GBGeorge M. BurslemKaiser Permanente

Key Points

The study aims to investigate the effects of VVD-065, a new molecular glue, on the control of NRF2 by KEAP1.
VVD-065 binds covalently to KEAP1 at Cys151.
Assembly of KEAP1-CUL3 is enhanced to promote NRF2 degradation.
The effects on NRF2-driven tumors were assessed.
VVD-065 restored NRF2 ubiquitination and degradation.
Enhanced KEAP1-CUL3 assembly was observed.
NRF2-driven tumors were selectively suppressed.

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.

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Cite This Study

Hintzen et al. (Fri,) studied this question.

synapsesocial.com/papers/69f6e60f8071d4f1bdfc6b44 https://doi.org/https://doi.org/10.1158/2159-8290.cd-26-0342

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