Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells.
Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells.
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DOI：
10.1021/acs.jmedchem.1c02179
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发表时间：
2022-04-14
影响因子：
7.3
通讯作者：
Hodgkinson JT
中科院分区：
文献类型：
--
作者：
Smalley JP;Baker IM;Pytel WA;Lin LY;Bowman KJ;Schwabe JWR;Cowley SM;Hodgkinson JT
第一类组蛋白去乙酰化酶（HDAC）酶1、2和3在七种不同的多蛋白协同抑制因子复合物中作为催化亚基组织染色质，并且是确定的药物靶点。我们报道了基于苯酰胺的Von Hippel-Lindau (VHL) e3连接酶蛋白水解靶向嵌合体（PROTACs）的优化研究，并首次描述了这些降解物引起的转录组扰动。通过修饰连接体和VHL配体，我们在HCT116细胞中鉴定出HDAC1和/或HDAC3具有亚微摩尔DC50值的PROTACs 7、9和22。观察到HDAC3的钩效应，可以通过改变VHL配体与连接体的附着位置来消除。HCT116细胞中，更强效的hdac /2降解物与更多的总差异表达基因和增强的凋亡相关。我们证明，HDAC1/2被PROTACs降解与增强的全局基因表达和细胞凋亡相关，这对于开发更有效、副作用更小的HDAC治疗方法很重要。
Class I histone deacetylase (HDAC) enzymes 1, 2, and 3 organize chromatin as the catalytic subunits within seven distinct multiprotein corepressor complexes and are established drug targets. We report optimization studies of benzamide-based Von Hippel–Lindau (VHL) E3-ligase proteolysis targeting chimeras (PROTACs) and for the first time describe transcriptome perturbations resulting from these degraders. By modifying the linker and VHL ligand, we identified PROTACs 7, 9, and 22 with submicromolar DC50 values for HDAC1 and/or HDAC3 in HCT116 cells. A hook effect was observed for HDAC3 that could be negated by modifying the position of attachment of the VHL ligand to the linker. The more potent HDAC1/2 degraders correlated with greater total differentially expressed genes and enhanced apoptosis in HCT116 cells. We demonstrate that HDAC1/2 degradation by PROTACs correlates with enhanced global gene expression and apoptosis, important for the development of more efficacious HDAC therapeutics with reduced side effects.
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