Design and Synthesis of Substrate Peptidomimetic Inhibitors (SPIs): New Probes for Epigenetic Target Validation

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The aim of the proposed research is to develop a novel type of synthetic molecule that will allow validation of epigenetic enzymes as therapeutic targets in oncology and provide lead compounds to initiate anticancer drug discovery programmes. The target proteins include deubiquitinase (DUB) and histone deacetylase (HDAC) enzymes.We will develop peptidomimetics based on the natural peptide substrates of the enzymes. Using advance, automated synthetic chemistry techniques we will produce a range of molecules that target Zn-dependent DUBs and class 1 HDACs with unprecedented selectivity. These molecules will have two main applications 1) as isozyme selective inhibitors to determine the mechanistic role of these enzymes in a cellular context (ex. their role in gene expression), 2) as tool molecules to facilitate advanced structural biology studies (ex. protein identification within complexes using cryo-EM).The insights gained from these experiments will be used to validate these enzymes as therapeutic targets, and inform structure-based design of selective inhibitors.