Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2021

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

Résumé

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 (K(i) = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with K(i) 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.

Domaines

Chimie
Fichier principal
Vignette du fichier
Pallesen-2021-Deconstructing Non-Covalent Kelch-like ECH-Associated Protein 1 Keap1.pdf (3.07 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03223155 , version 1 (15-11-2021)

Identifiants

Citer

Jakob S Pallesen, Dilip Narayanan, Kim T Tran, Sara M Ø Solbak, Giuseppe Marseglia, et al.. Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. Journal of Medicinal Chemistry, 2021, 64 (8), pp.4623-4661. ⟨10.1021/acs.jmedchem.0c02094⟩. ⟨hal-03223155⟩
112 Consultations
188 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More