Structure-based discovery of selective BRPF1 bromodomain inhibitors.

Zhu J; Zhou C; Caflisch A

doi:10.1016/j.ejmech.2018.05.037

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Journal article

Structure-based discovery of selective BRPF1 bromodomain inhibitors.

Zhu J Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Zhou C Department of Pathology, Shanghai University of Traditional Chinese Medicine, Cailun Road 1200, Pudong District, Shanghai, China.
Caflisch A Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.

2018-06-15

Published in:

European journal of medicinal chemistry. - 2018

Isothermal titration calorimetry

Adaptor Proteins, Signal Transducing

Dose-Response Relationship, Drug

Structure-Activity Relationship

English 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-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 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 = 3 μM), and the 2,4-dimethyl-oxazole derivative 42 (KD = 10 μM). 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.

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