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

Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related 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 fragment-based deconstruction reconstruction (FBDR) study tested four orthogonal assays. This gave 17 fragment hits which shown by X-ray crystallography bind Keap1 Kelch binding pocket. Two merged compound 8 with 220-380-fold stronger affinity (Ki = 16 ?M) relative parent fragments. Systematic optimization resulted several novel analogues Ki values 0.04-0.5 ?M, modes determined crystallography, enhanced microsomal stability. demonstrates how FBDR can be used find new hits, elucidate important ligand-protein interactions, identify potent PPI.