ArticleCancer discovery2026
A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth.
Article in Cancer discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05954312 (A Phase 1, Open-label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of VVD-130037, a Kelch-like ECH Associated Protein 1), which is not on this map. Cited by 19 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1, Open-label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of VVD-130037, a Kelch-like ECH Associated Protein 1 (KEAP1) Activator, in Participants With Advanced Solid Tumors
Who cites it
19 citing papers in PubMed.
- A Perspective on Covalent Hit Identification and Validation in the European Pharmaceutical Industry.Chembiochem : a European journal of chemical biology · 2026Article
- Recent advancements in NRF2-regulated ferroptosis modulation for targeted cancer therapy.Molecular biology reports · 2026Review
- Evading disulfidptosis via NRF2 translation.Nature cell biology · 2026Article
- Sulforaphane Decreases the Burden of AKT1-Expressing Pre-Neoplastic Cells in a Zebrafish Model of Glioblastoma Initiation.Nutrients · 2026Article
- Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging structural and functional evidence.Archives of biochemistry and biophysics · 2026Review
- Drug Discovery of Allosteric Molecular Glue Degraders (aMGDs): Expanding the Landscape of Targeted Protein Degradation.Journal of medicinal chemistry · 2026Article
- AbioRxiv : the preprint server for biology · 2026Article
- Pan-cancer proteogenomic interrogation of the ubiquitin-proteasome system.Cell death and differentiation · 2026Article
- Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.Acta pharmaceutica Sinica. B · 2026Review
- Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.Molecular metabolism · 2026Article
- Tipping the balance: NRF2's dual role in ferroptotic fate.Oncogenesis · 2026Review
- Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System.bioRxiv : the preprint server for biology · 2026Article
- Turning KEAP1 against NRF2.Nature chemical biology · 2026Article
- Pyrimethamine Restores KEAP1-Mediated Degradation of Select NRF2 Mutants in Esophageal Squamous Cell Carcinoma.Cancers · 2026Article
- Normalizing Covalent Potency for Electrophilicity with Ligand Reactivity Efficiency.Journal of medicinal chemistry · 2026Review
- Targeting NRF2 addiction in cancer: synthetic lethal strategies beyond direct inhibition.Frontiers in cell and developmental biology · 2026Review
- Wise as a Serpent and Gentle as a Dove: Pharmacological Targeting of NRF2/KEAP1 Pathway from Treasure Trove of Mother Nature.Drug design, development and therapy · 2026Review
- Ubiquitin E3 ligase KLHL6 brings exhausted T-cells back into action.Immunity & inflammation · 2026Article
- Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies.Cancers · 2025Review
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41 authors.
Funding
Abstract
The NRF2 transcription factor is constitutively active in cancer, in which it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2 dependency and resistance to chemotherapy/radiotherapy (RT). In this study, we characterize 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 Kelch-like ECH-associated protein 1 (KEAP1)-cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemotherapy/RT, supporting an open phase I clinical trial (NCT05954312). SIGNIFICANCE: NRF2 hyperactivation is frequently observed in various solid tumors, including lung, esophageal, and head and neck cancers, highlighting NRF2 as a potential therapeutic target. We report a first-in-class KEAP1-dependent allosteric molecular glue degrader of NRF2, which demonstrated robust monotherapy responses in NRF2-activated cancers and effectively sensitized chemo-refractory tumors to chemotherapy. See related commentary by Hintzen and Burslem, p. 829.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.