9HWS

Crystal structure of the Keap1 Kelch domain in complex with the small molecule UCAB#909 at 1.61 Angstrom resolution

This is a non-PDB format compatible entry.

Summary for 9HWS

• Entry DOI: 10.2210/pdb9hws/pdb
• Descriptor: Kelch-like ECH-associated protein 1, 3-[7-[2-(cycloheptylamino)-2-oxidanylidene-ethoxy]naphthalen-2-yl]propanoic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: keap1, nrf2, oxidative stress, inhibitor, peptide binding protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 34872.58

Authors

Narayanan, D.,Bach, A.,Gajhede, M. (deposition date: 2025-01-06, release date: 2025-09-03, Last modification date: 2025-10-08)

Primary citation

Lin, C.,Narayanan, D.,Barreca, M.,Poulsen, C.,da Costa, L.S.,Chen, X.,Wichman, K.G.,Charley, C.A.,Lindsay, J.L.,Dezfouli, M.,Vlissari, D.,Mortensen, T.S.,Chan, C.B.,Wang, J.,Richardson, W.,Manning, C.E.,Chen, Z.,Zang, J.,Kack, H.,Gajhede, M.,Bullock, A.N.,Blake, D.J.,Olagnier, D.,Bach, A.
Fragment-Based Drug Discovery of Novel High-affinity, Selective, and Anti-inflammatory Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction.
Angew.Chem.Int.Ed.Engl., 64:e202508121-e202508121, 2025

PubMed Abstract: Activating the cytoprotective response of nuclear factor erythroid 2-related factor 2 (Nrf2) can reduce oxidative stress and inflammation. A promising strategy is to inhibit the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 using noncovalent compounds that target the Keap1 Kelch domain. These compounds may be more specific than covalent Keap1-reacting Nrf2 activators. However, the development of drug-like noncovalent Keap1-Nrf2 inhibitors faces challenges due to the size and polarity of the Kelch binding pocket. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed from a weak fragment hit identified by crystallographic screening. A two-step growing strategy and optimization guided by several X-ray cocrystal structures led to compounds with low nanomolar affinities and complete selectivity for Keap1 in a panel of homologous Kelch domains. In cells, compounds 24 and 28 potently activated the expression of Nrf2-controlled genes and showed anti-inflammatory effects by downregulating NLRP3 inflammasome and STING signalling activation. RNA sequencing revealed activation of cytoprotective pathways and a different profile from typical covalent Nrf2 activators. This work highlights the potential of fragment-based drug discovery for challenging targets like Keap1 and introduces novel Keap1-Nrf2 inhibitors as chemical probes and drug leads.

PubMed: 40838516
DOI: 10.1002/anie.202508121

Experimental method

X-RAY DIFFRACTION (1.61 Å)