A Step toward NRF2‐DNA Interaction Inhibitors by Fragment‐Based NMR Methods

• DOI: 10.1002/cmdc.202100458
• Publication Date: 2021-09-15T15:40:39Z
• Authors: Sven Brüschweiler; Julian E. Fuchs; Gerd Bader; Darryl B. McConnell; Robert Konrat; Moriz Mayer
• Keywords: 0301 basic medicine; Small Molecule Libraries/chemistry; NF-E2-Related Factor 2; Nuclear Magnetic Resonance; 106002 Biochemie; NRF2; Small Molecule Libraries; PROTEIN-PROTEIN INTERACTIONS; Structure-Activity Relationship; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Protein Domains; MAGNETIC-RESONANCE; Humans; Nuclear Magnetic Resonance, Biomolecular; NF-E2-Related Factor 2/antagonists & inhibitors; 0303 health sciences; Binding Sites; Molecular Structure; CRYSTALLOGRAPHY; structure-activity relationships; 106002 Biochemistry; fragment screening; protein-DNA interactions; NMR solution structures; DNA; PERFORMANCE; Protein Binding/drug effects; Full Papers; 3. Good health; DNA-BINDING DOMAIN; Molecular Docking Simulation; TRANSCRIPTION FACTORS; ligand docking; DISCOVERY; SDG 3 – Gesundheit und Wohlergehen; LIGANDS; CHEMICAL-SHIFTS; SMALL-MOLECULE INHIBITORS; DNA/antagonists & inhibitors; Biomolecular; Protein Binding

AbstractThe 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.