Selective inhibitors of deubiquitylases

去泛素化酶的选择性抑制剂

基本信息

批准号：
8647347
负责人：
Mark Mason
金额：
$ 22.5万
依托单位：
LIFESENSORS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647347
关键词：
Active Sites Alzheimer&apos s Disease Amino Acids Autoimmune Diseases Autophagocytosis Binding Binding Sites Biological Models Biology Blood coagulation C-terminal Carbon Catalytic Domain Cathepsins Cell physiology Cephalosporins Chemicals Communicable Diseases Communities Cysteine Cysteine Protease Development Disease Distal Drug Targeting Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Event Excision Exhibits Factor XIa Factor Xa Family Generations Genes Glycine Goals Growth Half-Life Human Human Genome Hydrogen Inhibitory Concentration 50 Knock-out Lactams Lead Leukocyte Elastase Libraries Life Link Lysine Malignant Neoplasms Measures Modification Multienzyme Complexes Nature Pathway interactions Penicillins Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Physiological Play Polyubiquitin Positioning Attribute Post-Translational Protein Processing Proteins RNA Interference Reagent Receptor Mediated Signal Transduction Recording of previous events Regulation Research Role Series Serine Proteinase Inhibitors Specificity System Testing Therapeutic Intervention Tryptase Ubiquitin Ubiquitination Validation amino group base carboxylate caspase-3 cell growth regulation combinatorial drug development drug discovery falls human disease inhibitor/antagonist isopeptidase kinase inhibitor meetings multicatalytic endopeptidase complex programs protein degradation public health relevance receptor recycling scaffold screening small molecule success suicide inhibitor tool ubiquitin-aldehyde ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): In the last decade there has been an explosive growth in the field of ubiquitin research, with approximately 530 human genes predicted to encode enzymes involved in the conjugation and deconjugation of ubiquitin. Of these 95 encode deubiquitylases (DUBs) and these enzymes have become the target of many on-going drug discovery efforts. All DUBs carry-out the enzymatic removal of ubiquitin (Ub) from target proteins, whether that protein is a normal cellular protein or is Ub itself. Deconjugation requires the cleavage of an isopeptide bond formed between the C-terminus of Ub and the ¿-NH2-group of a Lys residue in the target protein. With the exception of the JAMM-family of DUBs, all DUBs fall into the peptidase C19 family and have an activated cysteine residue in the active site. As a consequence, most screening programs have a high hit rate of cys-reactive compounds that show low selectivity and potency. The most potent DUB inhibitors are generally produced by incorporation of a cys-reactivity moiety at the C-terminus of Ub, e.g. Ub-aldehyde, Ub-vinylsulfone, Ub-vinylmethylester. By their very nature, i.e. relying on the binding of Ub to the enzyme, such inhibitors exhibit little or no selectivity between different DUBs. The field of Ub research and the validation of DUBs as targets for drug discovery efforts, would be dramatically advanced by the availability of selective, high potency inhibitors of specific DUBs. In this application, we propose to develop panels of such inhibitors. In order to achieve high potency, we will take advantage of the reactivity of the active site cysteine through the use of a ¿-lactam scaffold. Attack on the lactam ring by the active site Cys leads to the generation of a stable tetrahedral intermediate. Selectivity is obtained by the substituents used to decorate the ring. This approach has been used by others to produce highly selective inhibitors of a number of enzymes, e.g. the blood coagulation enzymes activated factor X (FXa) and activated factor XI (FXIa), leukocyte elastase, tryptase, and cathepsins. It should be noted that the cathepsins are cysteine proteases, demonstrating that lactam-based inhibitors will function against this mechanistic class. Although our primary goal in this project is to generate a new series of research tools, the compounds that we produce could be used as lead compounds for drug development. Finally, the SAR that we develop around these compounds can be used to guide Medicinal Chemistry efforts around other compounds.

描述（由申请人提供）：在过去的十年中，泛素研究领域出现了爆炸性增长，预计有大约 530 个人类基因编码参与泛素缀合和解缀合的酶，其中 95 个编码去泛素化酶 (DUB)。这些酶已成为许多正在进行的药物发现工作的目标。所有 DUB 均通过酶法去除泛素 (Ub)。目标蛋白，无论该蛋白是正常细胞蛋白还是 Ub 本身都需要。 Ub 的 C 端和 ¿ 之间形成的异肽键的裂解目标蛋白中赖氨酸残基的-NH2-基团除了 DUB 的 JAMM 家族外，所有 DUB 均属于肽酶 C19 家族，并且在活性位点具有活化的半胱氨酸残基。筛选程序对半胱氨酸反应性化合物的命中率很高，但选择性和效力较低。最有效的 DUB 抑制剂通常是通过在 C 末端掺入半胱氨酸反应性部分来产生的。就其本质而言，即依赖于 Ub 与酶的结合，此类抑制剂在不同的 Ub 研究和领域中表现出很少或没有选择性。通过特定 DUB 的选择性高效抑制剂的可用性，将极大地推进 DUB 作为药物发现工作目标的验证。在本申请中，我们建议开发组合。为了实现高效力，我们将通过使用 ¿ 来利用活性位点半胱氨酸的反应性。活性位点 Cys 对内酰胺环的攻击导致稳定的四面体中间体的生成，这是通过用于装饰环的取代基获得的。酶的数量，例如凝血酶激活因子 X (FXa) 和激活因子 XI (FXIa)、白细胞弹性蛋白酶、类胰蛋白酶和组织蛋白酶。指出组织蛋白酶是半胱氨酸蛋白酶，这表明基于内酰胺的抑制剂将针对这种机制发挥作用，尽管我们在该项目中的主要目标是生成一系列新的研究工具，但我们可以生产的化合物可以用作。最后，我们围绕这些化合物开发的 SAR 可用于指导其他化合物的药物化学工作。