9hwq
Crystal structure of the Keap1 Kelch domain in complex with the XChem fragment Z19735904 at 1.14 Angstrom resolution.
Structural highlights
FunctionKEAP1_MOUSE Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).[1] [2] Publication Abstract from PubMedActivating 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. Fragment-Based Drug Discovery of Novel High-affinity, Selective, and Anti-inflammatory Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction.,Lin C, Narayanan D, Barreca M, Poulsen C, da Costa LS, Chen X, Wichman KG, Charley CA, Lindsay JL, Dezfouli M, Vlissari D, Mortensen TS, Chan CB, Wang J, Richardson W, Manning CE, Chen Z, Zang J, Kack H, Gajhede M, Bullock AN, Blake DJ, Olagnier D, Bach A Angew Chem Int Ed Engl. 2025 Aug 21:e202508121. doi: 10.1002/anie.202508121. PMID:40838516[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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