Selective inhibitors of ubiquitin E3 ligase to treat high cholesterol

泛素 E3 连接酶选择性抑制剂治疗高胆固醇

基本信息

批准号：
8930989
负责人：
David E Sterner
金额：
$ 61.17万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-19 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930989
关键词：
Adult Adverse effects Adverse reactions Affect American Animal Model Area Benefits and Risks Binding Biochemical Biological Assay Blood Blood Circulation Cardiovascular Diseases Cells Chemicals Cholesterol Cytoplasmic Tail Development Disease Drug Industry Drug Kinetics Drug Targeting Drug usage Dyslipidemias Enzymes Face Family Fingers Goals Health Heart Diseases Hepatic Hydroxymethylglutaryl-CoA reductase In Vitro Individual Knock-out Knockout Mice LDL Cholesterol Lipoproteins Laboratories Lead Ligase Low Density Lipoprotein Receptor Low-Density Lipoproteins Marketing Measures Modeling Mus Mutation Nature Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physicians Physiological Population Progress Reports Property Proteins Receptor Up-Regulation Regulation Reporting Resistance development Risk Risk Factors Serum Testing Therapeutic Therapeutic Agents Ubiquitin Validation Work analog base cardiovascular disorder risk cholesterol control drug discovery drug metabolism heart disease risk high throughput screening hypercholesterolemia improved in vivo inhibitor/antagonist interest meetings multicatalytic endopeptidase complex novel pre-clinical prevent receptor receptor upregulation small molecule targeted treatment therapeutic target ubiquitin-protein ligase uptake

Adult Adverse effects Adverse reactions Affect American Animal Model Area Benefits and Risks Binding Biochemical Biological Assay Blood Blood Circulation Cardiovascular Diseases Cells Chemicals Cholesterol Cytoplasmic Tail Development Disease Drug Industry Drug Kinetics Drug Targeting Drug usage Dyslipidemias Enzymes Face Family Fingers Goals Health Heart Diseases Hepatic Hydroxymethylglutaryl-CoA reductase In Vitro Individual Knock-out Knockout Mice LDL Cholesterol Lipoproteins Laboratories Lead Ligase Low Density Lipoprotein Receptor Low-Density Lipoproteins Marketing Measures Modeling Mus Mutation Nature Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physicians Physiological Population Progress Reports Property Proteins Receptor Up-Regulation Regulation Reporting Resistance development Risk Risk Factors Serum Testing Therapeutic Therapeutic Agents Ubiquitin Validation Work analog base cardiovascular disorder risk cholesterol control drug discovery drug metabolism heart disease risk high throughput screening hypercholesterolemia improved in vivo inhibitor/antagonist interest meetings multicatalytic endopeptidase complex novel pre-clinical prevent receptor receptor upregulation small molecule targeted treatment therapeutic target ubiquitin-protein ligase uptake

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项目摘要

DESCRIPTION (provided by applicant): Hypercholesterolemia is a major risk factor in cardiovascular diseases; it is estimated that >35 million individuals in the U.S. (or one-sixth of the adult population) have high total cholesterol and thus twice the risk of heart disease compared to those with optimal cholesterol levels. While statins are widely prescribed for cholesterol lowering, their serious side effect profile makes the risk/benefit consideration an important factor in a physician's decision to prescribe them. In addition, single agent statins are susceptible to the development of resistance in patients. Thus a need exists for new drugs that differ from statins in their therapeutic mechanisms; such drugs used singly have the potential to cause fewer side effects than statins but, more important, they could be used in combination with existing agents to prevent facile development of resistance. Nearly all cholesterol lowering drugs are directed at increasing the activity of the LDL Receptor (LDLR), which is primarily responsible for clearing cholesterol from the serum; this physiological endpoint can be achieved through a number of biochemically distinct mechanisms. Progenra's Phase I therapeutic hypothesis proposed to increase LDLR activity by maximizing its population utilizing the ubiquitin-proteasome pathway, a novel area for drug discovery. The posited therapeutic target, Idol, is a RING finger E3-ubiquitin ligase that conjugates ubiquitin to the LDLR on its cytoplasmic domain, resulting in its subsequent degradation; inhibitors of this ligase would effectively increase the average levels of LDLR. The pharmacologic outcome would be a reduction is the serum cholesterol level, and LDLR up-regulation is an established approach for cholesterol lowering. In fact, a recent study demonstrated increased LDLR in mouse Idol-knockout models. An Idol inhibitor would accomplish this therapeutic step by a completely novel mechanism. In addition, a selective inhibitor of Idol would be likely to produce minimal side effects. In Phase I, therefore, a high throughput screening assay for inhibitors of Idol was established and validated, and a screen was conducted on a set of small molecules. Several suitable hits were obtained in this screen. In Phase II it is proposed to perform chemical optimization on hits validated for potency and selectivity and initiate preclinical development of selected optimized analogues using (1) biochemical and cell-based secondary assays; and (2) animal models of drug metabolism/pharmacokinetic properties and LDL clearance (efficacy). The purpose of Phase II is to identify potent and selective compounds with efficacy as cholesterol-lowering therapeutic agents.

描述（由申请人提供）：高胆固醇血症是心血管疾病的主要危险因素；据估计，与最佳胆固醇水平的人相比，美国（或成年人口的六分之一）> 3500万个人（或成年人口的六分之一）的总胆固醇高，因此是心脏病的风险的两倍。尽管他汀类药物被广泛开处方用于降低胆固醇，但其严重的副作用使风险/福利考虑成为医生决定开处方的重要因素。此外，单位代理他汀类药物是容易受到患者耐药性的发展。因此，在其治疗机制中与他汀类药物不同的新药物存在需求。与他汀类药物相比，使用的这种药物可能会单独产生较少的副作用，但更重要的是，它们可以与现有药物结合使用以防止耐药性易于发展。几乎所有降低胆固醇的药物都旨在增加LDL受体（LDLR）的活性，LDL受体（LDLR）主要负责从血清中清除胆固醇。可以通过多种生化不同的机制来实现该生理终点。 Gepenra的I期治疗假说提出，通过利用泛素 - 蛋白酶体途径来最大化其种群，这是一种新颖的药物发现领域，从而提高了LDLR活性。所假定的治疗靶标，是一种环手指E3-泛素连接酶，将泛素结合到LDLR的细胞质结构域，从而导致其随后的降解。该连接酶的抑制剂将有效地增加LDLR的平均水平。药理学结果将是降低的是血清胆固醇水平，而LDLR上调是降低胆固醇的既定方法。实际上，最近的一项研究表明，小鼠偶像敲除模型中的LDLR增加。偶像抑制剂将通过一种完全新颖的机制实现这一治疗步骤。另外，偶像的选择性抑制剂可能会产生最小的副作用。因此，在第一阶段，建立了和验证了偶像抑制剂的高通量筛选测定法，并在一组小分子上进行了筛选。在此屏幕上获得了几个合适的命中。在第二阶段，建议对使用（1）生化和基于细胞的次级测定的临床前进行临床前的临床前进行验证，并启动所选优化类似物的临床前开发；（2）药物代谢/药代动力学特性和LDL清除率（功效）的动物模型。 II期的目的是将具有疗效的有效化合物确定为降低胆固醇的治疗剂。