7P5N

Pyrazole Carboxylic Acid Inhibitors of KEAP1:NRF2 interaction

Summary for 7P5N

• Entry DOI: 10.2210/pdb7p5n/pdb
• Descriptor: Kelch-like ECH-associated protein 1, CHLORIDE ION, 1-[3-[(1~{R},3~{S})-3-[(2~{R})-2-butylpyrrolidin-1-yl]carbonylcyclohexyl]phenyl]-5-cyclopropyl-pyrazole-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: protein ubiquitination, protein-protein interaction, oxidative stress, protein binding
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 35750.44

Authors

Davies, T.G. (deposition date: 2021-07-14, release date: 2021-11-17, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.89 Å)