ALDH1a1 Inhibition As A Therapeutic Target In Visceral Adiposity and Type 2 Diabetes

抑制 ALDH1a1 作为内脏肥胖和 2 型糖尿病的治疗靶点

基本信息

批准号：
10197108
负责人：
Patrick Robert Griffin
金额：
$ 49万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-21 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197108
关键词：
Adipose tissue Adult Antidiabetic Drugs Atherosclerosis Attention Biological Biological Assay Biology Body Weight decreased Body mass index Brown Fat Cell Line Characteristics Chemicals Chronic Complications of Diabetes Mellitus Coupled Crystallization Crystallography Data Deuterium Development Diabetes Mellitus Diet Dyslipidemias Eating Energy Intake Environment Enzymes Event Fat Body Fatty Acids Fatty Liver Fatty acid glycerol esters Fostering Future Genes Genetic Gluconeogenesis Goals Hand Heart Human Hydrogen Hypertension In Vitro Inflammation Injections Lead Liver Mediator of activation protein Medical Metabolic Metabolism Modeling Modernization Modification Mus National Institute of Diabetes and Digestive and Kidney Diseases Nervous System control Neuraxis Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacology Process Reporting Retinaldehyde Retinoids Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Thermogenesis Tretinoin Validation Visceral Visceral fat Vitamin A Work aldehyde dehydrogenases analog base clinically relevant design diabetic diet-induced obesity drug development energy balance hepatic gluconeogenesis improved in vitro testing in vivo in vivo Model in vivo evaluation inhibitor/antagonist insight interest intraperitoneal lead candidate lipid biosynthesis mRNA Expression meetings mimetics nanomolar new therapeutic target novel obese person programs response retinaldehyde dehydrogenase scaffold small molecule small molecule inhibitor small molecule libraries subcutaneous therapeutic target tool uncoupling protein 1 uptake

项目摘要

Obesity is a known driver of type 2 diabetes (T2D) and diabetic complications. While white adipose tissue (WAT) stores energy, brown adipose tissue (BAT), through the action of uncoupling protein 1 (UCP1) and a larger thermogenic program, releases energy as heat. BAT is now known to be present and modifiable in adult humans, including the prospect of inducing BAT-like characteristics in WAT (‘browning'). Loss of retinaldehyde dehydrogenase 1 (ALDH1a1) function potently induces UCP1, causing browning of WAT and protecting against diet-induced obesity and diabetes, as first we, and subsequently others, have shown in multiple in vivo models. Unlike many BAT-activating targets, ALDH1a1 inhibition decreases both subcutaneous and visceral adipose tissue (VAT), although its higher expression in visceral fat does foster pronounced effects in this particularly pathogenic depot. Independent of adiposity, ALDH1a1 deficiency also decreases hepatic gluconeogenesis and steatosis, common T2D abnormalities. ALDH1a1 converts the substrate retinaldehyde (Rald) to retinoic acid (RA). In vitro, either ALDH1a1 inhibition or direct Rald stimulation modulates expression of key thermogenic and gluconeogenic mediators. Data supports a relationship between ALDLH1a1 levels and adiposity in humans. Thus, a strong rationale exists for pursuing ALDH1a1 as a novel therapeutic target for decreasing adiposity and improving T2D, as our interdisciplinary, multiple PI team has undertaken, resulting in the strong preliminary data underlying this application. Aim 1 seeks to optimize, further develop, and test already identified lead small molecule ALDH1a1 inhibitors and Rald mimetics. Initial focus will be on four ALDH1a1 scaffold lead candidates found in our primary chemical library screen (650,000 compounds/validated ALDH1a1 activity assay/nanomolar IC50) using iterative chemical analysis and structural modifications coupled to in vitro and in vivo testing. Since the metabolic benefits of ALDH1a1 inhibition involve increased Rald levels, a novel, orthogonal therapeutic strategy explored here involves synthetic Rald mimetics; lead analogs are already designed, made and induce UCP1 expression. Hydrogen/deuterium exchange (HDX) and ALDH1a1 co-crystallography will also be leveraged to generate additional insights into ALDH1a1 modulator structure-activity relationships. Aim 2, tightly integrated with Aim 1 compound progression, will test the functional in vitro and in vivo effects of lead ALDH1a1 modulators on diabetes through changes in thermogenesis, energy balance, gluconeogenesis and steatosis. Taken together, ALDH1a1 modulation is well matched to this NIDDK PAR seeking “early-stage pharmacological validation of novel targets and pre- therapeutic leads”: a new pathway with compelling, validated prior data establishing clinically-relevant, unique effects on critical, unaddressed pathogenic diabetic mechanisms; an interdisciplinary, collaborative team with the requisite background and tools for the proposed work; extensive progress to date, including lead compounds that support ALDH1a1 inhibition as a potential therapeutic target for treating T2D.

肥胖是2型糖尿病（T2D）和糖尿病并发症的已知驱动因素。白色脂肪组织（WAT）储存能量，而棕色脂肪组织（BAT），通过解偶联蛋白1（UCP1）的作用和较大的热生效程序，将能量作为热量释放。现在众所周知，蝙蝠在成年人中存在和修改，包括在WAT（'Browning'）中引起类似蝙蝠的特征的前景。视网膜脱氢酶1（ALDH1A1）功能的丧失可能诱导UCP1，导致WAT褐变，并预防饮食诱导的肥胖和糖尿病，就像我们首先在多个体内模型中显示的那样。与许多蝙蝠激活靶标不同，ALDH1A1的抑制作用均下降了皮下和内脏脂肪组织（VAT），尽管其在内脏脂肪中较高的表达确实在这个特别的致病仓库中促进了明显的作用。与肥胖无关，ALDH1A1缺乏症也降低了肝肝脏发生和脂肪变性，常见的T2D异常。 ALDH1A1将底物残留醛（RALD）转换为视黄酸（RA）。在体外，ALDH1A1抑制或直接RALD刺激调制的调制表达了关键的热和谷歌介质的表达。数据支持人类的AldlH1A1水平与肥胖之间的关系。这是一个强大的理由，因为我们追求ALDH1A1作为降低肥胖和改善T2D的新型热目标，因为我们的跨学科，多个PI团队已经进行了，从而产生了该应用程序的强大初步数据。 AIM 1试图优化，进一步发展和测试已经确定已经识别的小分子ALDH1A1抑制剂和Rald Mimetics。最初的重点将用于使用迭代化学分析和结构修饰，与体外和体内测试结合结构修饰。由于ALDH1A1抑制的代谢益处涉及RALD水平增加，因此这里探索的一种新颖的正交理论策略涉及合成的Rald Mimetics。铅类似物已经设计，制造并诱导UCP1表达。还将利用氢/氘交换（HDX）和ALDH1A1共结晶术，以产生对ALDH1A1调节剂结构活性关系的其他见解。 AIM 2与AIM 1化合物进展紧密整合在一起，将通过热生成，能量平衡，牙lut肌和脂肪变化的变化来测试铅ALDH1A1调节剂对糖尿病的体外和体内作用。综上所述，ALDH1A1调制与此NIDDK PAR非常匹配，寻求“对新目标和治疗前的铅的早期药物验证”：一种新的途径，具有引人入胜的，经过验证的先前数据，对临床上的临床，未经良好的，未经认可的致病性糖尿病机制建立了临床上，独特的效果；一个跨学科的合作团队，具有必要的背景和拟议工作的工具；迄今为止的广泛进展，包括支持ALDH1A1作为治疗T2D的潜在治疗靶标的铅化合物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intact vitamin A transport is critical for cold-mediated adipose tissue browning and thermogenesis.

DOI：
10.1016/j.molmet.2020.101088
发表时间：
2020-12
期刊：
Molecular metabolism
影响因子：
8.1
作者：
Fenzl A;Kulterer OC;Spirk K;Mitulović G;Marculescu R;Bilban M;Baumgartner-Parzer S;Kautzky-Willer A;Kenner L;Plutzky J;Quadro L;Kiefer FW
通讯作者：
Kiefer FW

BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs.

DOI：
10.1161/circresaha.120.315929
发表时间：
2020-04-24
期刊：
Circulation research
影响因子：
20.1
作者：
Borck PC;Guo LW;Plutzky J
通讯作者：
Plutzky J

DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

DOI：
10.1016/j.jdiacomp.2021.108101
发表时间：
2022-02
期刊：
JOURNAL OF DIABETES AND ITS COMPLICATIONS
影响因子：
3
作者：
Handelsman, Yehuda;Anderson, John E.;Bakris, George L.;Ballantyne, Christie M.;Beckman, Joshua A.;Bhatt, Deepak L.;Bloomgarden, Zachary T.;Bozkurt, Biykem;Budoff, Matthew J.;Butler, Javed;Dagogo-Jack, Samuel;de Boer, Ian H.;DeFronzo, Ralph A.;Eckel, Robert H.;Einhorn, Daniel;Fonseca, Vivian A.;Green, Jennifer B.;Grunberger, George;Guerin, Chris;Inzucchi, Silvio E.;Jellinger, Paul S.;Kosiborod, Mikhail N.;Kushner, Pamela;Lepor, Norman;Mende, Christian W.;Michos, Erin D.;Plutzky, Jorge;Taub, Pam R.;Umpierrez, Guillermo E.;Vaduganathan, Muthiah;Weir, Matthew R.
通讯作者：
Weir, Matthew R.

The Aging Aorta: Are We Only as Old as Our Endothelium?