6ZEX

Keap1 kelch domain bound to a small molecule fragment

Summary for 6ZEX

• Entry DOI: 10.2210/pdb6zex/pdb
• Descriptor: Kelch-like ECH-associated protein 1, DIMETHYL SULFOXIDE, 5-cyclopropyl-1-phenyl-pyrazole-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: keap1, nrf2, oxidative stress, small molecule complex, peptide binding protein
• Biological source: Mus musculus (House mouse)
• Total number of polymer chains: 1
• Total formula weight: 34059.34

Authors

Narayanan, D.,Bach, A.,Gajhede, M. (deposition date: 2020-06-16, release date: 2021-04-14, Last modification date: 2024-01-24)

Primary citation

Pallesen, J.S.,Narayanan, D.,Tran, K.T.,Solbak, S.M.O.,Marseglia, G.,Sorensen, L.M.E.,Hoj, L.J.,Munafo, F.,Carmona, R.M.C.,Garcia, A.D.,Desu, H.L.,Brambilla, R.,Johansen, T.N.,Popowicz, G.M.,Sattler, M.,Gajhede, M.,Bach, A.
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.
J.Med.Chem., 64:4623-4661, 2021

PubMed Abstract: 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 with a 220-380-fold stronger affinity ( = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with 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.

PubMed: 33818106
DOI: 10.1021/acs.jmedchem.0c02094

Experimental method

X-RAY DIFFRACTION (1.98 Å)