Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome

这项研究的目的是开发一种新型的分子，这种分子将允许验证一种称为去泛素化酶（DUB）的酶家族作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。DUB通过从其他蛋白质中去除称为泛素的小调节蛋白在细胞中发挥重要作用。人类基因组编码约80种去泛素化酶（DUB/DUB样）。这个酶家族包含五个亚家族，其中四个已经被研究和靶向。剩下的一组被称为锌依赖性DUB，由于缺乏可用于探测其功能的分子，因此尚未成为目标。我们已经建立了一个专家团队，在各自的研究领域（Echalier -结构生物学，Jamieson -肽化学和Kessler -蛋白质质谱）开发基于酶的天然肽底物的此类分子。使用现代合成化学技术，我们的目标是产生一系列分子，以前所未有的选择性靶向锌依赖性DUBs。从这些实验中获得的见解将用于验证它们作为治疗靶点，并为选择性DUB抑制剂的基于结构的药物设计提供信息。

The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme.DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function.We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.