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

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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.