ArticleChemMedChem2021
A Step toward NRF2-DNA Interaction Inhibitors by Fragment-Based NMR Methods.
Article in ChemMedChem, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- Strategies for Identifying Molecules of Interest in Large Chemical Spaces.Journal of chemical information and modeling · 2026Article
- Genotypic and Phenotypic Diversity as a Function of CRISPR-Directed Gene Knock-Out ofBiomolecules · 2026Article
- Pyrimethamine Restores KEAP1-Mediated Degradation of Select NRF2 Mutants in Esophageal Squamous Cell Carcinoma.Cancers · 2026Article
- Investigating Potential 5' UTR G-Quadruplexes Within NRF2 mRNA.Current issues in molecular biology · 2026Article
- cGAS Downregulation Contributes to EGFR-TKI Resistance in NSCLC through the p-Nrf2-SIRT3-ROS/Ferroptosis Axis.Oncology research · 2026Article
- Nrf2 signaling in bone health: unlocking new avenues for osteoporosis management.Inflammopharmacology · 2025Review
- NRF2 activation in cancer and overview of NRF2 small molecule inhibitors.Archives of pharmacal research · 2025Review
- Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The NRF2 transcription factor is a key regulator in cellular oxidative stress response, and acts as a tumor suppressor. Aberrant activation of NRF2 has been implicated in promoting chemo-resistance, tumor growth, and metastasis by activating its downstream target genes. Hence, inhibition of NRF2 promises to be an attractive therapeutic strategy to suppress cell proliferation and enhance cell apoptosis in cancer. Direct targeting of NRF2 with small-molecules to discover protein-DNA interaction inhibitors is challenging as it is a largely intrinsically disordered protein. To discover molecules that bind to NRF2 at the DNA binding interface, we performed an NMR-based fragment screen against its DNA-binding domain. We discovered several weakly binding fragment hits that bind to a region overlapping with the DNA binding site. Using SAR by catalogue we developed an initial structure-activity relationship for the most interesting initial hit series. By combining NMR chemical shift perturbations and data-driven docking, binding poses which agreed with NMR information and the observed SAR were elucidated. The herein discovered NRF2 hits and proposed binding modes form the basis for future structure-based optimization campaigns on this important but to date 'undrugged' cancer driver.
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Registered trials
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.