Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery.

一类表观遗传阅读器域Bromodomain和Extra-terminal（BET）蛋白已经成为小分子药物发现的一种有希望的新靶标，可用于治疗癌症，炎性疾病和自身免疫性疾病。从计算机筛选运动开始，本文报道了基于[1,2,4]三唑并[4,3- a ]喹喔啉骨架的新型BET抑制剂的发现及其生物学评估。使用药物化学方法对命中化合物进行优化，以使其在结合测定中对BRD4具有出色的抑制活性。铅化合物具有重要的抗人癌细胞增殖活性，有前途的药物样特性以及对BET家族的选择性（13）作为抗癌药物发现的新型BRD4抑制剂基序。