Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).
Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).
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DOI：
10.1021/acs.biochem.2c00288
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发表时间：
2023-02-07
期刊：
影响因子：
2.9
通讯作者：
Cowley, Shaun M.
中科院分区：
文献类型：
--
作者：
Baker, India M.;Smalley, Joshua P.;Sabat, Khadija A.;Hodgkinson, James T.;Cowley, Shaun M.
I类组蛋白脱乙酰基酶（HDAC）酶; HDAC 1、2和3形成细胞中至少七种结构上不同的多蛋白复合物的催化引擎。这些分子机器通过从组蛋白尾部内的赖氨酸残基去除乙酰基部分在调节染色质可及性和基因活性中起着至关重要的作用。通过小分子抑制剂对它们的抑制在许多疾病类型中具有有益效果，包括血液癌症的临床治疗。我们先前已经报道了蛋白水解靶向嵌合体（PROTAC）的文库，其包含基于苯甲酰胺的HDAC配体（来自CI-994），具有用于von Hippel-Lindau（VHL）E3泛素连接酶的烷基接头和配体，其在亚微摩尔浓度下降解HDAC 1 -3。在这里，我们报告了两个新的PROTAC（JPS 026和JPS 027），利用E3连接酶的细胞凋亡抑制剂（IAP）家族的配体。我们发现基于VHL（JPS 004）和IAP（JPS 026）的PROTAC降解HDAC 1 -3并诱导组蛋白乙酰化至相似的程度。然而，JPS 026在诱导HCT 116细胞中的细胞死亡方面比JPS 004显著更有效。PROTAC处理的HCT 116细胞的RNA测序分析显示了一个独特的基因表达特征，其中细胞周期和DNA复制机制受到抑制。mTORC 1和-2复合物的组分也减少，导致FOXO 3和调节自噬和凋亡的下游靶基因增加。总之，HDAC和IAP配体的新组合产生具有刺激人癌细胞中的细胞凋亡和差异基因表达的有效能力的PROTAC。
The class I histone deacetylase (HDAC) enzymes;HDAC1,2 and 3 form the catalytic engine of at least seven structurally distinct multiprotein complexes in cells. These molecular machines play a vital role in the regulation of chromatin accessibility and gene activity via the removal of acetyl moieties from lysine residues within histone tails. Their inhibition via small molecule inhibitors has beneficial effects in a number of disease types, including the clinical treatment of hematological cancers. We have previously reported a library of proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase that degrade HDAC1–3 at submicromolar concentrations. Here we report the addition of two novel PROTACs (JPS026 and JPS027), which utilize a ligand for the cellular inhibitor of apoptosis (IAP) family of E3 ligases. We found that both VHL (JPS004)- and IAP (JPS026)-based PROTACs degrade HDAC1–3 and induce histone acetylation to a similar degree. However, JPS026 is significantly more potent at inducing cell death in HCT116 cells than is JPS004. RNA sequencing analysis of PROTAC-treated HCT116 cells showed a distinct gene expression signature in which cell cycle and DNA replication machinery are repressed. Components of the mTORC1 and -2 complexes were also reduced, leading to an increase in FOXO3 and downstream target genes that regulate autophagy and apoptosis. In summary, a novel combination of HDAC and IAP ligands generates a PROTAC with a potent ability to stimulate apoptosis and differential gene expression in human cancer cells.
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1504021112
发表时间：
2015-07-14
影响因子：
11.1
作者：
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通讯作者：
Radhakrishnan, Ishwar
影响因子：
5.6
作者：
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通讯作者：
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