Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors
Inhibition of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as an attractive approach for treating oxidative stress-related diseases. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed by a conformational restriction strategy of our fluorenone-based compounds previously identified by fragment-based drug discovery. The design was guided by X-ray cocrystal structures, and the subsequent optimization process aimed at improving affinity, cellular activity, and metabolic stability. From the noncyclic compound <b>7</b> (<i>K</i><sub>i</sub> = 2.9 μM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (<b>57</b>, <i>K</i><sub>i</sub> = 13 nM), better metabolic stability, and enhanced cellular activity was obtained. In addition, the compounds showed selectivity for the Keap1 Kelch domain across a panel of 15 homologous proteins. We thereby demonstrate the utility of cyclic rigidification in the design of potent and more drug-like Keap1-Nrf2 inhibitors.
Authors
- Michael Gajhede (ORCID: https://orcid.org/0000-0001-9864-2287)
- David Olagnier (ORCID: https://orcid.org/0000-0001-6912-0674)
- Elina Mukminova
- Dilip Narayanan (ORCID: https://orcid.org/0000-0001-9164-9961)
- Chun‐Yu Lin (ORCID: https://orcid.org/0000-0002-6818-4681)
- Camilla B. Chan
- Yuting Qin (ORCID: https://orcid.org/0009-0002-6692-8648)
- Anders Bach (ORCID: https://orcid.org/0000-0003-4305-9910)
- Alex N. Bullock (ORCID: https://orcid.org/0000-0001-6757-0436)
- Cecilie Poulsen
- Xiangrong Chen (ORCID: https://orcid.org/0000-0003-0587-3444)
- Beatriz Ralsi Montes (ORCID: https://orcid.org/0009-0003-3263-0883)
- Kim T. Tran
Institutions
- University of Copenhagen (DK)
- Aarhus University (DK)
- Novo Nordisk Foundation (DK)
- Nuffield Orthopaedic Centre (GB)
- University of Oxford (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01221
- Citations
- 14
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- Kræftens Bekæmpelse
- Hørslev-Fonden
- Diamond Light Source
- European Federation of Pharmaceutical Industries and Associations
- VINNOVA
- Svenska Forskningsrådet Formas
- Lundbeckfonden
- Kungliga Tekniska Högskolan
- China Scholarship Council
- Danmarks Frie Forskningsfond
- Eva og Henry Frænkels Mindefond
- Novo Nordisk Fonden
- Hartmann Fonden
- Fabrikant Einar Willumsens Mindelegat
- Innovative Medicines Initiative
- Horizon 2020 Framework Programme