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.

项目概要识别新疗法的策略通常包括针对相关相关酶活性生物途径，假设该方法最有可能识别出有效的、安全的和生物可利用的这个概念与组蛋白等表观遗传干扰物的发展特别相关。脱乙酰酶 (HDAC) 抑制剂，或“HDACis” FDA 批准的所有七种 HDACis 以类似的方式结合。虽然这种“酶抑制剂”化合物已被成功使用。在治疗 T 细胞淋巴瘤和多发性骨髓瘤方面，它们在治疗其他类型的癌症方面仍然有限。目前可用的 HDAC 的主要局限性之一是，通过系统地靶向 HDAC 酶口袋中，它们对负责调节不同的 HDAC 复合体几乎没有表现出特异性。基因的子集，因此，它们影响大部分基因的转录调控我们的目标是开发一种替代模型，根据该模型“蛋白质相互作用”。 “调节剂”扰乱 HDAC 子复合物子集中的特定蛋白质相互作用，因此具有很多作用与传统的 HDACis 相比，它对处理细胞的转录组的影响更窄。模型的观点是，扰动特定的 HDAC 子复合体而不是细胞中的所有 HDAC 复合体可能会导致更窄的转录效应，但仍具有有效的抗肿瘤作用（图1）。假设，我们提出以下三个具体目标。目标 1. 确定非酶亚基的小分子扰动程度 HDAC 复合物可以影响其抑制功能。我们的目标是确定一类新的 HDAC。调节剂，它不是针对酶袋，而是影响 HDAC 的其他更具体的功能复合物。目标 2. 比较 HDAC 非酶促与酶促小分子的整体转录组效应我们中心假设的一个分支是应该可以识别 HDAC。复杂的调节剂导致比传统观察到的转录效应窄得多 HDAC 酶抑制剂在这里我们将确定 HDAC 亚复合物调节剂的转录组范围的影响。研究这些新化合物对转录组的影响有多广或多窄。目标 3. 检验以下假设：HDAC 复合物的启动子占据扰动可以有效地我们将测试对特定 HDAC 子复合物的干扰程度。比所有细胞 HDAC 复合体，虽然导致转录效应窄得多，但可能赋予有效的抗肿瘤作用。简而言之，我们建议不要像传统 HDAC 抑制剂那样影响细胞中的所有 HDAC 活性，可以鉴定出一类新的蛋白质相互作用调节剂，其影响特定的 HDAC 子复合物。