Chemical Tools for Probing Histone Deacetylase Multiprotein Complexes in Disease

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The development of new chemical tools and probes is vital to understanding the functions of multifaceted proteins and enzymes in the cell and their role in disease. Many enzymes catalyse chemical modifications to DNA and DNA associated proteins regulating which genes are 'switched on' and 'off', often termed the epigenome. Histone deacetylases (HDAC) are a class of enzyme that remove acetyl groups from DNA associated histone proteins. The presence of many HDAC isoenzymes in the cell, with structural similarity, makes probing these enzymes selectively a challenge. Further to this, the same HDAC isoenzyme can be incorporated as a catalytic sub-unit into a number of much larger multiprotein corepressor complexes, whereby the complex is essential to the distinct biological function of the HDAC. Abnormal HDAC activity is associated with diseases including cancer and Alzheimer's yet current drugs lack HDAC enzyme selectivity and are associated with debilitating side effects.The proposed research will deliver novel chemical tools designed to modulate HDAC enzymes with multiprotein complex selectivity. Designing compounds to selectively target a specific HDAC complex is a novel approach towards probing the function of such complexes with significant therapeutic potential. This will be achieved by three objectives. Objective one involves the preparation of dual functionalised warhead peptides designed to bind two enzymatic sites simultaneously in a specific complex. Objective two focuses on the development of compounds to facilitate selective degradation of a sub-unit enzyme required for multiprotein complex structural integrity and function. Objective three broadens on the approaches from objective two investigating the synthesis and validation of other compounds to degrade other histone deacetylase enzymes with complex selectivity. The chemical tools developed will have important applications in studying the roles of HDAC multiprotein complexes in disease, and the tools will also be used for future medicinal compound development to treat diseases such as cancer.