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Structural analysis of human KDM5B guides histone demethylase inhibitor development

DOI: 10.1038/nchembio.2087 DOI Help

Authors: Catrine Johansson (Structural Genomics Consortium Oxford, University of Oxford, U.K.) , Velupillai Srikannathasan (Structural Genomic Consortium, Oxford) , Anthony Tumber (University of Oxford) , Aleksandra Szykowska (University of Oxford) , Edward S Hookway (University of Oxford) , Radoslaw Nowak (University of Oxford) , Claire Strain-damerell (University of Oxford) , Carina Gileadi (University of Oxford) , Martin Philpott (University of Oxford) , Nicola Burgess-brown (University of Oxford) , Na Wu (University of Oxford) , Jolanta Kopec (University of Oxford) , Andrea Nuzzi (University of Oxford) , Holger Steuber (Bayer Healthcare Pharmaceuticals) , Ursula Egner (Bayer Healthcare Pharmaceuticals) , Volker Badock (Bayer Healthcare Pharmaceuticals) , Shonagh Munro (University of Oxford) , Nicholas B Lathangue (University of Oxford) , Sue Westaway (GlaxoSmithKline R&D) , Jack Brown (GlaxoSmithKline R&D) , Nick Athanasou (University of Oxford) , Rab Prinjha (GlaxoSmithKline R&D) , Paul E Brennan (University of Oxford) , Udo Oppermann (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology

State: Published (Approved)
Published: May 2016
Diamond Proposal Number(s): 10619

Abstract: Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe2+-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25–100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography