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

拟议研究的目的是开发一种新型的合成分子，使表观遗传酶成为肿瘤学的治疗靶点，并提供先导化合物来启动抗癌药物发现计划。目标蛋白包括脱泛素酶(DUB)和组蛋白脱乙酰基酶(HDAC)。我们将在这些酶的天然多肽底物的基础上开发肽仿制。使用先进的自动化合成化学技术，我们将以前所未有的选择性生产一系列针对依赖锌的DUB和1类HDAC的分子。这些分子将有两个主要用途：1)作为同工酶选择性抑制剂，以确定这些酶在细胞环境中的机制作用(例如。它们在基因表达中的作用)，2)作为工具分子促进高级结构生物学研究(例如。从这些实验中获得的见解将被用于验证这些酶作为治疗靶点的有效性，并为选择性抑制剂的基于结构的设计提供信息。

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.