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.
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.
Insights
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.
