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

• 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
• 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

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，棕色脂肪组织(BAT)通过解偶联蛋白1(UCP1)和更大的生热程序释放能量。现在已知蝙蝠在成年人类中存在并可改变，包括在Wat(褐变)中诱导蝙蝠样特征的前景。视黄醛脱氢酶1(ALDH1A1)功能的丧失可以有效地诱导UCP1，导致Wat的褐变，并防止饮食诱导的肥胖和糖尿病，正如我们和后来的其他人在多种体内模型中所表明的那样。与许多蝙蝠激活靶点不同，抑制ALDH1A1可同时减少皮下和内脏脂肪组织(VAT)，尽管其在内脏脂肪中的较高表达确实在这一特别的病原体储存库中促进了显著的效果。与肥胖无关，ALDH1A1缺乏也会减少肝脏糖异生和脂肪变性，这是常见的T2D异常。ALDH1A1将底物视黄醛(RAD)转化为维甲酸(RA)。在体外，无论是ALDH1A1抑制还是直接RADD刺激，都可以调节关键的生热和生糖介质的表达。数据支持ALDLH1a1水平与人类肥胖之间的关系。因此，有很强的理由将ALDH1A1作为一种新的治疗靶点来减少肥胖和改善T2D，正如我们的跨学科、多PI团队所从事的那样，导致了这一应用的强大的初步数据。目标1旨在优化、进一步开发和测试已确定的铅小分子ALDH1A1抑制剂和RALD模拟物。最初的重点将是在我们的初级化学库筛选中发现的四个ALDH1A1支架候选铅(650,000种化合物/验证的ALDH1A1活性分析/纳米分子IC50)，使用迭代化学分析和结构修改，并结合体外和体内测试。由于ALDH1A1抑制的代谢益处涉及增加RAD水平，因此这里探索的一种新的、正交的治疗策略涉及合成RAD模拟物；已经设计、制造并诱导UCP1表达的铅类似物。氢/氚交换(HDX)和ALDH1A1共结晶学也将被用来产生对ALDH1A1调节剂结构-活性关系的更多见解。AIM 2与AIM 1化合物进展紧密结合，将通过改变产热、能量平衡、糖异生和脂肪变性来测试铅ALDH1A1调节剂在体外和体内对糖尿病的功能性影响。综上所述，ALDH1A1调制与NIDDK的这一PAR非常匹配，正在寻求“新靶点和治疗前线索的早期药理学验证”：一条具有令人信服的、经过验证的先前数据，建立了对关键的、未解决的致病糖尿病机制的临床相关、独特影响的新途径；一个跨学科的协作团队，具有拟议工作所需的背景和工具；迄今取得的广泛进展，包括支持将ALDH1A1抑制作为治疗T2D的潜在治疗靶点的先导化合物。

项目成果

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

BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.

• DOI: 10.26508/lsa.201900540
• 发表时间: 2021-01
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Shen H;Li J;Xie X;Yang H;Zhang M;Wang B;Kent KC;Plutzky J;Guo LW
• 通讯作者: Guo LW

BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs.

在心血管转录程序中赌注表观遗传读取器蛋白。

• 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.