6zb2 | pdb_00006zb2
C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH GSK549
Structural highlights
Function[BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1] Publication Abstract from PubMedThe profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100 fold) inhibition of a sub-set of the 8 bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimisation of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046) was the basis for the high selectivity observed. This culminated in two tool molecules 20 (GSK620) and 56 (GSK549) which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research. The Optimisation of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.,Seal JT, Atkinson SJ, Aylott H, Bamborough P, Chung CW, Copley RCB, Gordon LJ, Grandi P, Gray JRJ, Harrison LA, Hayhow TG, Lindon M, Messenger C, Michon AM, Mitchell DJ, Preston A, Prinjha RK, Rioja I, Taylor S, Wall ID, Watson RJ, Woolven JM, Demont EH J Med Chem. 2020 Jul 23. doi: 10.1021/acs.jmedchem.0c00796. PMID:32702236[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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