Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 155, Issue -, Pages 337-352Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.05.037
Keywords
BRPF1 bromodomain; Pharmacophore search; Structure-based drug design; X-ray crystallography; Isothermal titration calorimetry; Molecular dynamics
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Funding
- Swiss National Science Foundation [31003A_169007]
- Swiss National Science Foundation (SNF) [31003A_169007] Funding Source: Swiss National Science Foundation (SNF)
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Bromodomain 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-mu M 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 (K-D = 3 mu M), and the 2,4-dimethyl-oxazole derivative 42 (K-D = 10 mu M). 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. (C) 2018 Elsevier Masson SAS. All rights reserved.
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