Design, synthesis and characterization of covalent KDM5 inhibitors

Abstract: Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Angewandte Chemie. International Edition. - 58, 2 (2019) , 515-519, ISSN: 1433-7851

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2020
• Creator: Vazquez-Rodriguez, Saleta ; Wright, Miranda ; Rogers, Catherine ; Cribbs, Adam ; Velupillai, Srikannathasan ; Philpott, Martin ; Lee, Henry ; Dunford, James E. ; Huber, Kilian ; Robers, Matthew B. ; Vasta, James D. ; Thezenas, Marie-Laetitia ; Bonham, Sarah ; Kessler, Benedikt ; Bennett, James ; Fedorov, Oleg ; Raynaud, Florence ; Donovan, Adam ; Blagg, Julian ; Bavetsias, Vassilios ; Oppermann, Udo ; Bountra, Chas ; Kawamura, Akane ; Brennan, Paul E.
• Contributor: FRIAS Natur- und Lebenswissenschaften, Medizin und Ingenieurwissenschaften

Further information

• DOI: 10.1002/anie.201810179
• URN: urn:nbn:de:bsz:25-freidok-1523232
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:54 PM CET