5mwh | pdb_00005mwh
Crystal structure of the human BRPF1 bromodomain in complex with BZ089
Structural highlights
FunctionBRPF1_HUMAN Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. Positively regulates the transcription of RUNX1 and RUNX2.[1] [2] Publication Abstract from PubMedBromodomain and plant homeodomain (PHD) finger containing protein 1 (BRPF1) is a member of subfamily IV of the human bromodomains. Experimental evidence suggests that BRPF1 is involved in leukemia. In a previous high-throughput docking campaign we identified several chemotypes targeting the BRPF1 bromodomain. Here, pharmacophore searches using the binding modes of two of these chemotypes resulted in two new series of ligands of the BRPF1 bromodomain. The 2,3-dioxo-quinoxaline 21 exhibits a 2-muM affinity for the BRPF1 bromodomain in two different competition binding assays, and more than 100-fold selectivity for BRPF1 against other members of subfamily IV and representatives of other subfamilies. Cellular activity is confirmed by a viability assay in a leukemia cell line. Isothermal titration calorimetry measurements reveal enthalpy-driven binding for compounds 21, 26 (KD=3muM), and the 2,4-dimethyl-oxazole derivative 42 (KD=10muM). Multiple molecular dynamics simulations and a dozen co-crystal structures at high resolution provide useful information for further optimization of affinity for the BRPF1 bromodomain. Structure-based discovery of selective BRPF1 bromodomain inhibitors.,Zhu J, Zhou C, Caflisch A Eur J Med Chem. 2018 Jun 2;155:337-352. doi: 10.1016/j.ejmech.2018.05.037. PMID:29902720[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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