- 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 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.
- Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
-
supporting information
p. 4623 - 4661
(2021/05/07)
-
- Boron trichloride as an efficient and selective agent for deprotection of tert-butyl aryl sulfonamides
-
A fast, mild and selective method for deprotection of tert-butyl aryl sulfonamides utilizing BCl3 as deprotection reagent has been developed. A variety of tert-butyl aryl sulfonamides used under these conditions gave the corresponding primary sulfonamides in high yields. The method does not cleave methoxy groups and prevents incorporation of tert-butyl groups onto electron-rich aromatic rings.
- Wan, Yiqian,Wu, Xiongyu,Kannan, Mahalingam A.,Alterman, Mathias
-
p. 4523 - 4525
(2007/10/03)
-
- Catalytic Properties of Carbonyl Reductase from Rabbit Kidney for Acetohexamide and Its Analogs
-
Analogs submitted by ethyl, n-propyl, n-butyl, and isopropyl groups instead of methyl group adjacent to a ketone group of acetohexamide were synthesized and the structural requirements of carbonyl reductase from rabbit kidney for these analogs were kineti
- Imamura, Yorishige,Higuchi, Toshiyuki,Otagiri, Masaki,Nagumo, Shinji,Akita, Hiroyuki
-
p. 387 - 394
(2007/10/02)
-
- Process for the production of benzenesulfonamides
-
Process comprises the combination of two steps of interacting a R-benzene, sulfuric acid and phosphorus oxychloride to obtain 4-R-benzenesulfonyl chloride and amidating said sulfonyl chloride to produce 4-R-benzenesulfonamide.
- -
-
-