@article{a9238dfcf7e146a3856f5e315a6a5571,
title = "Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds",
abstract = "Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.",
author = "Pallesen, {Jakob S.} and Dilip Narayanan and Tran, {Kim T.} and Solbak, {Sara M.{\O}.} and Giuseppe Marseglia and S{\o}rensen, {Louis M.E.} and H{\o}j, {Lars J.} and Federico Munaf{\`o} and Carmona, {Rosa M.C.} and Garcia, {Anthony D.} and Desu, {Haritha L.} and Roberta Brambilla and Johansen, {Tommy N.} and Popowicz, {Grzegorz M.} and Michael Sattler and Michael Gajhede and Anders Bach",
note = "Funding Information: This research was supported by the Lundbeck Foundation (grant R190-2014-3710 for A.B.); the A. P. M{\o}ller Foundation for the Advancement of Medical Science (grant 14–28 for A.B.); the H{\o}rslev Foundation (grant 203866-MIA for A.B.); the Augustinus Foundation (grant 14-1571 for A.B.); and the Drug Research Academy/Lundbeck Foundation (scholarship for K.T.T.). We also acknowledge funding from the European Union{\textquoteright}s Framework Program for Research and Innovation Horizon 2020 (2014–2020) under the Marie Sk{\l}odowska-Curie Grant Agreement no. 675555, Accelerated Early staGe drug discovery (AEGIS) and the Helmholtz Center Munich to M.S. and G.M.P., and access to NMR measurements at the Bavarian NMR Center and at the University of Copenhagen (the latter supported by grant #10-085264 from The Danish Research Council for Independent Research|Nature and Universe and grant R77-A6742 from the Lundbeck Foundation). We thank all the staff at the European beamlines (BioMAX at MAX IV, Sweden; ID29 and ID30a at ESRF, France; and P13 and P14 at DESY, Germany) for beamtime and their support and help. Publisher Copyright: {\textcopyright} 2021 American Chemical Society. All rights reserved.",
year = "2021",
month = apr,
day = "22",
doi = "10.1021/acs.jmedchem.0c02094",
language = "English (US)",
volume = "64",
pages = "4623--4661",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",
}