7P5E

Pyrazole Carboxylic Acid Inhibitors of KEAP1:NRF2 interaction

7P5E の概要

• エントリーDOI: 10.2210/pdb7p5e/pdb
• 分子名称: Kelch-like ECH-associated protein 1, DIMETHYL SULFOXIDE, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: protein ubiquitination, protein-protein interaction, oxidative stress, protein binding
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35769.30

構造登録者

Davies, T.G.,Cleasby, A. (登録日: 2021-07-14, 公開日: 2021-11-17, 最終更新日: 2024-06-19)

主引用文献

Norton, D.,Bonnette, W.G.,Callahan, J.F.,Carr, M.G.,Griffiths-Jones, C.M.,Heightman, T.D.,Kerns, J.K.,Nie, H.,Rich, S.J.,Richardson, C.,Rumsey, W.,Sanchez, Y.,Verdonk, M.L.,Willems, H.M.G.,Wixted, W.E.,Wolfe 3rd, L.,Woolford, A.J.,Wu, Z.,Davies, T.G.
Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.
J.Med.Chem., 64:15949-15972, 2021

PubMed Abstract: The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

PubMed: 34705450
DOI: 10.1021/acs.jmedchem.1c01351

実験手法

X-RAY DIFFRACTION (1.874 Å)