Abstract

Bromodomains (BRDs) are important protein domains in the reading process of epigenetic marks. Recent studies have demonstrated that human BET protein BRD4 which contains bromodomains plays a critical role in cell proliferation, cancer growth and virus-host pathogenesis. In this work, a chemical-core substitution strategy was employed to identify BRD4 bromodomain inhibitors that had new and different chemical cores featuring common chemical portions with the parent fragments. After the combination of compounds BI2536 and GSK726, two hit compounds 6h and 6i represented potent lead compounds to deserve further optimization. Then, ten analogous compounds were synthesized and evaluated by in-vitro biological test. Among them, compound 6d exhibited the greatest inhibition against BRD4 bromodomains with IC50 _{value of 180 nM.}

Keywords: Epigenetic, BRD4, chemical-core substitution, quinoxalone derivatives, biology, optimization

Graphical Abstract