- 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
-
p. 4623 - 4661
(2021/05/07)
-
- Synthesis and spectroscopic characterization of 1-13C- and 4-13C-plastoquinone-9
-
This paper presents the synthesis of 1-13C- and 4-13C-plastoquinone-9 and their characterization with NMR spectroscopy and mass spectrometry. The synthetic scheme has been further adapted to introduce 13C-labeled plastoquinones on all individual and on each combination of positions in the quinone ring. Also a two-step scheme is disclosed to prepare unlabeled plastoquinone-9. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Boers, Rutger B.,Randulfe, Yolanda Pazos,Van Der Haas, Hendrikus N. S.,Van Rossum-Baan, Marleen,Lugtenburg, Johan
-
p. 2094 - 2108
(2007/10/03)
-