Selective disruption of histone deacetylase complexes using protein interaction modulators

使用蛋白质相互作用调节剂选择性破坏组蛋白脱乙酰酶复合物

基本信息

批准号：
10340227
负责人：
Marc Vidal
金额：
$ 68.09万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340227
关键词：
Address Affect Binding Biological Biological Models Cancer Death Rates Cell Line Cell physiology Cells Complex Data Deacetylase Development Enzymes Epigenetic Process FDA approved Future Generations Genes Genetic Transcription Goals Hematopoietic Neoplasms Histone Deacetylase Histone Deacetylase Inhibitor Human Human Pathology Immunotherapy In Vitro Invaded Learning Malignant Neoplasms Mammalian Cell Modeling Molecular Multiple Myeloma Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Property Proteins Public Health Regulation Reporter Reporter Genes Specificity Substrate Specificity T-Cell Lymphoma Testing Therapeutic Tissues Transcriptional Regulation Work Yeasts anti-cancer base cancer immunotherapy cancer type drug discovery experimental study immune checkpoint blockade improved in vivo inhibitor neoplastic cell neuroblastoma cell novel novel strategies novel therapeutics paralogous gene promoter protein complex small molecule small molecule libraries targeted cancer therapy targeted treatment transcriptome transcriptomics tumorigenesis tumorigenic

项目摘要

Project Summary Strategies to identify novel therapeutics typically include targeting enzymatic activities involved in relevant biological pathways, with the assumption that this approach will most likely identify potent, safe, and bioavailable drugs. This concept is particularly relevant to the development of epigenetic perturbants such as histone deacetylase (HDAC) inhibitors, or “HDACis”. All seven FDA-approved HDACis bind in similar ways to promiscuous deacetylase enzymatic pockets. While such “enzymatic inhibitor” compounds are used successfully to treat T cell lymphomas and multiple myelomas, they remain limited in addressing other types of cancers. One of the major limitations of currently available HDACis is that, by systematically targeting HDAC enzymatic pockets, they show little specificity for various HDAC complexes responsible for the regulation of different subsets of genes, and consequently, they affect the transcriptional regulation of a large portion of the transcriptome. Our goal here is to develop an alternative model according to which “protein interaction modulators” perturb specific protein interactions in subsets of HDAC subcomplexes and thus have much narrower effects on the transcriptome of treated cells than conventional HDACis. The central hypothesis of this model is that perturbing specific HDAC subcomplexes rather than all HDAC complexes in a cell might result in much narrower transcriptional effects and yet confer potent anti-tumorigenic effects (Fig. 1). To test this hypothesis, we propose the three following specific aims. Aim 1. To determine the extent to which small-molecule perturbations of non-enzymatic subunits of HDAC complexes can affect their repressing functions. Our goal is to identify a new class of HDAC modulators, which, instead of targeting enzymatic pockets, would affect other, more specific functions of HDAC complexes. Aim 2. To compare global transcriptomic effects of HDAC non-enzymatic versus enzymatic small- molecule perturbations. One branch of our central hypothesis is that it should be possible to identify HDAC complex modulators that result in much narrower transcriptional effects than those observed with conventional HDAC enzymatic inhibitors. Here we will determine transcriptome-wide effects of HDAC subcomplex modulators to investigate how widely or narrowly these new compounds affect the transcriptome. Aim 3. To test the hypothesis that promoter occupancy perturbations of HDAC complexes can potently abrogate tumorigenic phenotypes. We will test to what extent perturbing specific HDAC subcomplexes rather than all cellular HDAC complexes, while resulting in much narrower transcriptional effects, might nevertheless confer potent anti-tumorigenic effects. In short, we propose that instead of affecting all HDAC activities in the cell as conventional HDAC inhibitors do, a new class of protein interaction modulators can be identified that affect specific HDAC subcomplexes.

项目摘要鉴定新疗法的策略通常包括针对相关涉及的酶促活动生物学途径，假设这种方法最有可能确定潜力，安全和生物利用毒品。这个概念与表观遗传扰动者（例如组蛋白）的发展特别相关脱乙酰基酶（HDAC）抑制剂或“ HDACIS”。所有七个FDA批准的HDACIS都以类似的方式结合混杂的脱乙酰基酶酶袋。尽管成功使用了这种“酶抑制剂”化合物为了治疗T细胞淋巴瘤和多个脊髓瘤，它们在解决其他类型的癌症方面仍然有限。当前可用的HDACI的主要局限性之一是，通过系统地靶向HDAC酶促口袋，它们对负责调节的各种HDAC复合物的特异性几乎没有基因的子集，因此，它们影响了大部分的转录调控转录组。我们的目标是根据“蛋白质相互作用”开发替代模型调节剂”在HDAC亚复合体子集中的扰动特异性蛋白质相互作用，因此具有很多对处理细胞的转录组的影响窄，而不是常规HDACIS。中心假设模型是扰动特定的HDAC亚复合物而不是细胞中的所有HDAC复合物可能会导致转录效应较窄，但赋予潜在的抗肿瘤效应（图1）。测试这个假设，我们提出了以下三个特定目的。目的1。确定非酶亚基的小分子扰动的程度 HDAC复合物可以影响其反射功能。我们的目标是确定新的HDAC类调节剂，而不是靶向酶促袋，而是会影响HDAC的其他更具体的功能复合物。目的2。比较HDAC非酶与酶小的全球转录组效应分子扰动。我们中心假设的一个分支是应该可以识别HDAC 复杂的调节器会导致转录效应要窄得多，比传统 HDAC酶抑制剂。在这里，我们将确定HDAC子复合调节器的全转录组效果研究这些新化合物影响转录组的宽度或狭窄。目的3。检验以下假设：HDAC复合物的启动子占用扰动可能有可能废除肿瘤性表型。我们将测试特定特定的HDAC子复合物而不是在多大程度上测试比所有蜂窝HDAC复合物都产生了较窄的转录效应，但仍可能会议有效的抗肿瘤效应。简而言之，我们建议，而不是像常规的HDAC抑制剂那样影响细胞中的所有HDAC活性，而是可以鉴定出一类新的蛋白质相互作用调节剂，以影响特定的HDAC亚复合物。