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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：
8648310
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648310
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 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 public health relevance receptor receptor upregulation small molecule therapeutic target ubiquitin-protein ligase uptake

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，美国有3500万人（占成年人口的六分之一）总胆固醇过高，因此与胆固醇水平最佳的人相比，患心脏病的风险是他们的两倍。虽然他汀类药物被广泛用于降低胆固醇，但其严重的副作用使得风险/收益考虑成为医生决定开处方的重要因素。此外，单药他汀类药物