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Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue

GSE278482 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2025/01/03 Platform GPL16791
Summary
The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we developed VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently adducts C151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to dramatic enhancement of NRF2 degradation. Previously reported C151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).
Published in
A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth
Roy N, Wyseure T, Lo IC et al. · Cancer discovery 2026 · PMID 41417010 · doi:10.1158/2159-8290.CD-25-1187
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Direct links to NCBI, no account and no request form: the whole study as GSE278482_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 8 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1167342 and SRA study SRP535835. Searching any of these in the dataset finder brings you back here.

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