A Step toward NRF2-DNA Interaction Inhibitors by Fragment-Based NMR Methods
Sven Brüschweiler1, Julian E Fuchs2, Gerd Bader2
1Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030, Vienna, Austria.
Chemmedchem
|September 15, 2021
Summary
Researchers identified small molecules that inhibit the NRF2 protein, a key driver in cancer. This discovery offers a new therapeutic strategy for cancer treatment by targeting NRF2's DNA binding site.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- The NRF2 transcription factor regulates oxidative stress response and tumor suppression.
- Aberrant NRF2 activation promotes chemo-resistance, tumor growth, and metastasis.
- Inhibiting NRF2 is a promising strategy to suppress cancer cell proliferation and enhance apoptosis.
Purpose of the Study:
- To discover small molecules that inhibit the NRF2 protein at its DNA binding interface.
- To develop structure-activity relationships for identified NRF2 inhibitors.
- To provide a basis for structure-based drug design against NRF2.
Main Methods:
- NMR-based fragment screening of the NRF2 DNA-binding domain.
- Structure-activity relationship (SAR) studies using SAR by catalogue.
- NMR chemical shift perturbations and data-driven docking to elucidate binding poses.
Main Results:
- Several weakly binding fragment hits were identified at the NRF2 DNA binding interface.
- An initial structure-activity relationship was established for fragment hits.
- Binding poses consistent with NMR data and SAR were elucidated.
Conclusions:
- Discovered novel small-molecule NRF2 inhibitors targeting the DNA binding interface.
- Established initial SAR and binding modes for NRF2 inhibitors.
- These findings provide a foundation for developing NRF2-targeted cancer therapeutics.
