According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.

根据ABBV-744与溴结构域的结合方式以及HDAC的空位，通过药效基团融合策略设计合成了新型选择性HDAC / BRD4双重抑制剂。通过SAR评估评估生物分子活性，鉴定了三种选择性双重抑制剂41c（HDAC1 / BRD4），43a（pan -HDAC / BRD4）和43d（HDAC6 / BRD4（BD2）），它们在MV-4中具有靶标相关的细胞活性。还确认了-11个细胞。重要的是，选择性双重抑制剂41c（HDAC1 / BRD4）对MV-4-11细胞具有协同作用，可强烈诱导G0 / G1细胞周期阻滞和凋亡，并发现了第一个HDAC6 / BRD4（BD2）双重抑制剂。这项研究为选择性HDAC / BRD4双重抑制剂作为基于吡咯并吡啶酮核心的表观遗传学探针提供了支持，以便将来在不同癌细胞系中进行生物学评估。