发现选择性 HDAC/BRD4 双重抑制剂作为表观遗传探针。
Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.
机构信息
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
出版信息
Eur J Med Chem. 2021 Jan 1;209:112868. doi: 10.1016/j.ejmech.2020.112868. Epub 2020 Oct 13.
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 与溴结构域的结合模式和 HDAC 的帽空间，设计并合成了通过药效团融合策略设计的新型选择性 HDAC/BRD4 双重抑制剂。通过 SARs 探索评估生物分子活性，确定了三种选择性双重抑制剂 41c（HDAC1/BRD4）、43a（pan-HDAC/BRD4）和 43d（HDAC6/BRD4（BD2）），并在 MV-4-11 细胞中证实了其靶相关细胞活性。值得注意的是，选择性双重抑制剂 41c（HDAC1/BRD4）对 MV-4-11 细胞表现出协同作用，强烈诱导 G0/G1 细胞周期停滞和细胞凋亡，发现了第一个 HDAC6/BRD4（BD2）双重抑制剂。本研究为基于吡咯并吡啶酮核心的选择性 HDAC/BRD4 双重抑制剂作为表观遗传学探针提供了依据，为未来在不同癌细胞系中的生物学评价提供了支持。
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