Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degradation of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degradation effects for HDAC3 with a DC₅₀ value of 0.32 μM. In contrast to biochemical evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biological outcome.

组蛋白脱乙酰基酶（HDAC）在诸如哮喘和慢性阻塞性肺疾病（COPD）等炎性疾病中起重要作用。解开和干扰促发炎症的特定同工酶的功能为药物开发提供了机会。在这里，我们合成针对I类HDAC降解的针对嵌合体（PROTACs）的蛋白水解，其中基于o-氨基苯胺的I类HDAC抑制剂被束缚在脑神经配体pomalidomide上。这些PROTAC之一（称为HD-TAC7）对具有DC _50的HDAC3表现出可观的降解效果值为0.32μM。与使用siRNA的生化证据相反，HD-TAC7对LPS /IFNγ刺激的RAW 264.7巨噬细胞中的基因表达影响最小。缺乏这种作用可归因于NF-κB亚基p65的下调，这是波马利度胺治疗的已知副作用。总而言之，我们描述了一种新型的PROTAC，它能够选择性下调HDAC3的水平，但是我们注意到，NF-κB亚基p65的同时下调会混淆生物学结果。