Selective inhibitors of deubiquitylases

去泛素化酶的选择性抑制剂

• 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
• 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' 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

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）：在过去十年中，泛素研究领域出现了爆炸性增长，预计约有530种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都能从靶蛋白中酶促去除泛素（Ub），无论该蛋白是正常细胞蛋白还是Ub本身。解除共轭需要 Ub的C末端和靶蛋白中Lys残基的â-NH2-基团之间形成的异肽键的断裂。除了DUB的JAMM家族之外，所有DUB都属于肽酶C19家族，并且在活性位点中具有活化的半胱氨酸残基。因此，大多数筛选程序具有高命中率的cys反应性化合物，其显示低选择性和效力。最有效的DUB抑制剂通常通过在Ub的C末端掺入cys反应性部分来产生，例如Ub-醛、Ub-乙烯基砜、Ub-乙烯基甲酯。由于它们的本质，即依赖于Ub与酶的结合，这样的抑制剂在不同DUB之间表现出很少或没有选择性。Ub研究领域和DUB作为药物发现努力的目标的验证，将通过特定DUB的选择性高效抑制剂的可用性而显著推进。在本申请中，我们提出开发这样的抑制剂的面板。为了实现高效力，我们将通过使用<$-内酰胺支架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产生稳定的四面体中间体。选择性通过用于装饰环的取代基获得。这种方法已被其他人用于生产多种酶的高选择性抑制剂，例如凝血酶活化因子X（FXa）和活化因子XI（FXIa）、白细胞弹性蛋白酶、类胰蛋白酶和组织蛋白酶。应该注意的是，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该机制类别起作用。虽然我们在这个项目中的主要目标是产生一系列新的研究工具，但我们生产的化合物可以用作药物开发的先导化合物。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。