Developing Proteolysis Targeted Chimeras (PROTACs) toindividual class-I Histone Deacetylase complexes

组蛋白去乙酰化酶（HDAC）通过维持整个基因组中组蛋白乙酰化的水平和位置来调节染色质的可及性。因此，所有需要接触DNA的过程——转录、DNA复制、DNA修复和染色体分离——都受到HDAC活性的影响。i类hdac（1、2和3）作为不同多蛋白复合物（Sin3A、NuRD、CoREST、MiDAC和NCoR）的一部分发挥这一作用，有助于将其活性定向到特定位点并确定底物特异性。我们的长期目标是使用PROTAC方法开发针对这五种复合物的小分子抑制剂。蛋白水解靶向嵌合体（PROTAC）是一种异双功能分子，它将已知的结合片段结合到感兴趣的蛋白质（POI，例如抑制剂）上，并与E3泛素连接酶复合物的配体偶联。通过PROTAC将E3连接酶直接募集到POI上，使其泛素化并最终降解，从而下调其活性。该研究的目的是开发基于protac的新型工具，以在基础水平上询问单个i类HDAC复合物在细胞中的作用，并确定开发新型HDAC抑制剂的先导化合物。

Histone deacetylase (HDAC) enzymes regulate chromatin accessibility globally by maintaining the level and location of histone-acetylation across the genome. All processes that require access to DNA - transcription, DNA replication, DNA repair and chromosome segregation - are thus influenced by HDAC activity. The class-I HDACs (1, 2 and 3) perform this role as part of distinct multi-protein complexes (Sin3A, NuRD, CoREST, MiDAC and NCoR) which help direct their activity to specific loci and determine substrate specificity. Our long-term goal is to develop small-molecule inhibitors against each of these five complexes using a PROTAC approach. Proteolysis Targeting Chimaeras (PROTAC) are hetero-bifunctional molecules which incorporate a known binding moiety to the protein of interest (POI, e.g. an inhibitor), coupled to a ligand for an E3 ubiquitin ligase complex. Direct recruitment of the E3 ligase to the POI via the PROTAC, targets it for ubiquitination and ultimately degradation, thus down-regulating its activity. The aim of this studentship is to develop novel PROTAC-based tools to interrogate the roles of individual class-I HDAC complexes in cells at a fundamental level and identify lead compounds for the development of a new class of HDAC inhibitors.