Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes

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. (c) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

Selective HDAC/BRD4 dual inhibitors were designed and synthesized using pharmacophore fusion strategy, leading to the identification of three types of inhibitors with different cellular activities. Among them, the selective dual inhibitor 41c showed synergistic effects in inducing cell cycle arrest and apoptosis in MV-4-11 cells. This study supports the use of selective HDAC/BRD4 dual inhibitors as epigenetic probes for future biological evaluation in various cancer cell lines.