Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors

  • J Med Chem. 2024 Oct 17. doi: 10.1021/acs.jmedchem.4c01221.
Yuting Qin  1 ,  Cecilie Poulsen  2 ,  Dilip Narayanan  1 ,  Camilla B Chan  1  3 ,  Xiangrong Chen  4 ,  Beatriz Ralsi Montes  4 ,  Kim T Tran  1 ,  Elina Mukminova  1 ,  Chunyu Lin  1 ,  Michael Gajhede  1 ,  Alex N Bullock  4 ,  David Olagnier  2 ,  Anders Bach  1
Affiliations
  • 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2. Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus C, Denmark.
  • 3. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 4. Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
PMID: 39418396 DOI: 10.1021/acs.jmedchem.4c01221
Abstract

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 7 (Ki = 2.9 μM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (57, Ki = 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.

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