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

肥胖是2型糖尿病（T2 D）和糖尿病并发症的已知驱动因素。虽然白色脂肪组织（WAT）储存能量，但棕色脂肪组织（BAT）通过解偶联蛋白1（UCP 1）和更大的产热程序的作用，以热量的形式释放能量。现在已知BAT存在于成年人中并且是可改变的，包括在WAT中诱导BAT样特征（“褐变”）的前景。视黄醇脱氢酶1（ALDH 1a 1）功能的丧失有效地诱导UCP 1，导致WAT的布朗宁，并防止饮食诱导的肥胖和糖尿病，正如我们和随后的其他人在多个体内模型中所显示的。与许多BAT激活靶点不同，ALDH 1a 1抑制可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种特别致病的贮库中产生了显著的作用。与肥胖无关，ALDH 1a 1缺乏也会减少肝脏的新生和脂肪变性，常见的T2 D异常。ALDH 1a 1将底物视黄醇（Rald）转化为视黄酸（RA）。在体外，ALDH 1a 1抑制或直接Rald刺激调节关键产热和产热介质的表达。数据支持ALDLH 1a 1水平与人类肥胖之间的关系。因此，正如我们的跨学科、多PI团队所做的那样，将ALDH 1a 1作为减少肥胖和改善T2 D的新型治疗靶点是有充分理由的，从而产生了支持该应用的强有力的初步数据。目的1寻求优化、进一步开发和测试已经鉴定的先导小分子ALDH 1a 1抑制剂和Rald模拟物。最初的重点将是在我们的主要化学库筛选中发现的四种ALDH 1a 1支架先导候选物（650，000种化合物/经验证的ALDH 1a 1活性测定/纳摩尔IC 50），使用迭代化学分析和结构修饰结合体外和体内测试。由于ALDH 1a 1抑制的代谢益处涉及增加的Rald水平，因此在此探索的一种新的正交治疗策略涉及合成的Rald模拟物;已经设计、制造并诱导UCP 1表达的先导类似物。氢/氘交换（HDX）和ALDH 1a 1共结晶学也将被用来产生对ALDH 1a 1调节剂结构-活性关系的额外见解。目标2与目标1化合物进展紧密结合，将通过产热、能量平衡、脂肪生成和脂肪变性的变化来测试先导ALDH 1a 1调节剂对糖尿病的功能性体外和体内作用。总而言之，ALDH 1a 1调节与寻求“新靶点和治疗前线索的早期药理学验证”的NIDDK PAR非常匹配：一种新途径，具有令人信服的、经过验证的先前数据，对关键的、未解决的致病性糖尿病机制建立了临床相关的独特作用;一个跨学科的协作团队，拥有拟议工作所需的背景和工具;迄今为止取得了广泛的进展，包括支持ALDH 1a 1抑制的先导化合物作为治疗T2 D的潜在治疗靶点。

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.