School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Eur J Med Chem. 2022 Sep 5;239:114544. doi: 10.1016/j.ejmech.2022.114544. Epub 2022 Jun 21.
Overexpression of histone deacetylase 8 (HDAC8) is associated with various diseases such as cancer. Thus, compounds that can modulate HDAC8 levels have therapeutic potential for these diseases. Based on the proteolysis targeting chimera (PROTAC) strategy, we designed and synthesized a series of HDAC8 degraders by tethering an HDAC6/8 dual inhibitor with pomalidomide (a cereblon ligand). Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 with DC of 147 nM and D of 93%, and exhibited no effects on HDAC1 and HDAC3. Interestingly, we found that the degradation of target protein started at ∼2 h after treatment with ZQ-23 and the maximal degradation effect was achieved at 10 h. The HDAC8 level was partially recovered within 24 h. In addition, ZQ-23 had no degrading effects on HDAC1 and HDAC3 at all concentrations, but could dose-dependently increase the levels of acetylated SMC-3 (HDAC8 substrate). Mechanism study demonstrated that ZQ-23 degraded HDAC8 through the ubiquitin-protease pathway, rather than lysosome system. Collectively, these results suggest that ZQ-23 represents a novel PROTAC-based HDAC8 degrader worthy of further investigation.
组蛋白去乙酰化酶 8（HDAC8）的过表达与各种疾病有关，如癌症。因此，能够调节 HDAC8 水平的化合物在这些疾病中有治疗潜力。基于蛋白水解靶向嵌合体（PROTAC）策略，我们通过将 HDAC6/8 双重抑制剂与泊马度胺（cereblon 配体）连接，设计并合成了一系列 HDAC8 降解剂。其中，化合物 ZQ-23 对 HDAC8 表现出显著且选择性的降解作用，DC 为 147 nM，D 为 93%，对 HDAC1 和 HDAC3 没有影响。有趣的是，我们发现用 ZQ-23 处理后，靶蛋白的降解在约 2 h 开始，在 10 h 达到最大降解效果。在 24 h 内，HDAC8 水平部分恢复。此外，ZQ-23 在所有浓度下对 HDAC1 和 HDAC3 均无降解作用，但可剂量依赖性地增加乙酰化 SMC-3（HDAC8 底物）的水平。机制研究表明，ZQ-23 通过泛素蛋白酶体途径而不是溶酶体系统降解 HDAC8。总之，这些结果表明 ZQ-23 代表了一种新型的基于 PROTAC 的 HDAC8 降解剂，值得进一步研究。
