Structure-based discovery of selective BRPF1 bromodomain inhibitors

TitleStructure-based discovery of selective BRPF1 bromodomain inhibitors
Publication TypeJournal Article
Year of Publication2018
AuthorsZhu J., Zhou C., Caflisch A.
JournalEuropean Journal of Medicinal Chemistry
Start Page337
Issue155
Pagination337-352
Date PublishedMay 23 2018
Type of ArticleResearch Article
ISSN0223-5234
KeywordsBRPF1, Calorimetry, Crystallography, molecular dynamics, selective inhibitors, X-Ray
Abstract

Bromodomain and plant homeodomain (PHD) finger containing protein 1 (BRPF1) is a member of subfamily İV 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-μM affinity for the BRPF1 bromodomain in two different competition binding assays, and more than 100-fold selectivity for BRPF1 against other members of subfamily İV 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 = 3 μM), and the 2,4-dimethyl-oxazole derivative 42 (KD = 10μM). 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.

URLhttps://www.sciencedirect.com/science/article/pii/S0223523418304501
DOI10.1016/j.ejmech.2018.05.037
pubindex

0236

Alternate JournalEur. J. Med. Chem.
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