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.
BT - European Journal of Medicinal Chemistry C1 - 0236 DA - May 23 2018 DO - 10.1016/j.ejmech.2018.05.037 IS - 155 J2 - Eur. J. Med. Chem. LA - eng M3 - Research Article N2 -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.
PY - 2018 SE - 337 SP - 337 EP - 352 T2 - European Journal of Medicinal Chemistry TI - Structure-based discovery of selective BRPF1 bromodomain inhibitors UR - https://www.sciencedirect.com/science/article/pii/S0223523418304501 SN - 0223-5234 ER -