Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证

• 批准号: 10580851
• 负责人: Weidong Wang
• 金额: $ 46.01万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580851
• 关键词: Acetylation; Address; Adipocytes; Adopted; Adverse effects; Affinity; Agonist; Antidiabetic Drugs; Atherosclerosis; Binding; Binding Proteins; Biological Assay; Biological Availability; Biology; Body Weight; Body fat; Cells; Cellular Assay; Chemicals; Clinical; Deacetylase; Deacetylation; Diabetes Mellitus; Diabetes prevention; Drug Kinetics; Drug or chemical Tissue Distribution; Edema; Energy Metabolism; Epidemic; Excretory function; Exhibits; Fluid Balance; Gene Expression; Genes; Genetic; Goals; Half-Life; Heart; Heart Hypertrophy; Heart failure; Hormonal; In Vitro; Insulin; Insulin Resistance; Knock-in Mouse; Lead; Link; Liquid substance; Metabolic; Metabolic Diseases; Metabolism; Mus; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Obesity; PPAR gamma; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Prevalence; Prevention; Property; Reporting; Research; SIRT1 gene; Safety; Standardization; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Validation; Water; Weight Gain; Work; absorption; analog; bone; bone loss; clinical development; comorbidity; cost; design; diaries; diet-induced obesity; driving force; drug discovery; efficacy evaluation; glucose tolerance; improved; in vivo; in vivo evaluation; inhibitor; insulin sensitivity; insulin sensitizing drugs; lead candidate; mimetics; mouse model; novel; novel strategies; obesity genetics; pandemic disease; pharmacologic; pre-clinical; prototype; retention rate; side effect; small molecule; systemic toxicity; therapeutic target; therapy development; transcription factor

PROJECT SUMMARY This proposal aims to leverage basic discoveries in interdisciplinary fields to develop a novel and safer therapy for pandemic type 2 diabetes (T2D). Obesity-linked insulin resistance is the key driving force for T2D and other metabolic disorders. Despite the wide use of commonly used anti-diabetic drugs for T2D treatment, the prevalence of T2D continues to soar with an annual cost over $300 billion in the US. The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is an important therapeutic target for insulin sensitization and its full agonist TZD drugs are by far the most potent insulin-sensitizing drugs. However, TZD drugs are associated with adverse side effects including heart failure and weight gain, as TZD-induced full agonism of PPARγ activates not only the expression of genes responsible for insulin sensitizing but also of those genes associated with side effects, thereby severely hampering the clinical use of TZDs. Recent studies have indicated that PPARγ posttranslational modifications (PTMs) may lead to the selective activation of PPARγ target genes that results in the decoupling of the beneficial effects on insulin sensitizing from the TZD- related adverse effects. Our team recently discovered that deacetylation at K268 and K293 in PPARγ by the NAD+-dependent deacetylase SirT1 plays a key role in such decoupling. Excitingly, the PIs have developed a novel class of PPARγ agonist, TPMD, that bound to PPARγ to specifically inhibit PPAR acetylation. Importantly, TPMD improved insulin sensitivity and increased white-to-brown adipocyte conversion (browning) and energy expenditure without causing TZD-associated side effects in both genetic and diary obesity mouse models. In this application, the team led by the two PIs with complementary expertise in diabetes drug discovery and PPARγ biology will use TPMD as the starting molecule to identify the first-in-class inhibitor of PPARγ acetylation that exert potent insulin-sensitizing and browning activities and better safety and pharmacokinetic (PK) properties. In Aim 1, they will employ structure-based design through iterative and parallel medicinal chemistry to identify TPMD analogs with improved potency of inhibiting PPARγ acetylation. In Aim 2, the lead analogs will be proceeded to the standardized core in vitro ADMET assays and in vivo pharmacokinetics studies to select those with the most favorable pharmacological properties. In Aim 3, the lead candidates will be tested rigorously for their in vivo efficacy and safety in obesity and genetic mouse models. The PIs will adopt their “standardized” metabolic characterizations and assessments of TZD-associated adverse side effects. The proposed studies will produce first-in-class PPARγ acetylation inhibitors that have improved insulin-sensitizing potency, safety, and PK profiles. Thus, completion of this research will be well-poised for further clinical development to curtail the current epidemics of insulin resistance and T2D.

项目概要 该提案旨在利用跨学科领域的基本发现来开发一种新颖且更安全的疗法 对于大流行 2 型糖尿病 (T2D)，肥胖相关的胰岛素抵抗是 T2D 和其他疾病的关键驱动力。 尽管常用的抗糖尿病药物广泛用于 T2D 治疗，但 T2D 的患病率持续飙升，在美国每年造成的损失超过 3000 亿美元。 过氧化物酶体增殖物激活受体γ（PPARγ）是胰岛素的重要治疗靶点 增敏剂TZD及其完全激动剂是目前最有效的胰岛素增敏剂，但TZD。 与不良副作用药物有关，包括心力衰竭和体重增加，因为 TZD 引起的完全 PPARγ 的激动不仅激活负责胰岛素增敏的基因的表达，而且还激活 这些与副作用相关的基因严重阻碍了 TZD 的临床使用。 已经表明 PPARγ 翻译后修饰（PTM）可能导致选择性激活 PPARγ 靶基因导致胰岛素增敏的有益作用与 TZD- 脱钩 我们的团队最近发现 PPARγ 中 K268 和 K293 的脱乙酰作用 NAD+ 依赖性脱乙酰酶 SirT1 在这种解偶联中发挥着关键作用，令人兴奋的是，PI 已经开发出一种 新型 PPARγ 激动剂 TPMD 与 PPARγ 结合，特异性抑制 PPARγ 乙酰化。 TPMD 改善胰岛素敏感性并增加白色脂肪细胞转化（褐变）和能量 在遗传性和乳性肥胖小鼠模型中，支出不会引起 TZD 相关副作用。 该团队由两位 PI 领导，在糖尿病药物发现和 PPARγ 方面具有互补的专业知识 生物学将使用 TPMD 作为起始分子来鉴定一流的 PPARγ 乙酰化抑制剂， 发挥有效的胰岛素增敏和褐变活性以及更好的安全性和药代动力学（PK）特性。 在目标 1 中，他们将通过迭代和并行药物化学采用基于结构的设计来识别 TPMD 类似物具有改善的抑制 PPARγ 乙酰化的功效。在目标 2 中，主要类似物是。 继续进行核心的体外 ADMET 测定和体内药代动力学标准化研究，以选择那些 在目标 3 中，主要候选药物将接受严格的测试。 他们在肥胖和遗传小鼠模型中的体内功效和安全性 PI 将采用他们的“标准化”。 拟议的研究将进行 TZD 相关不良副作用的代谢特征和评估。 生产一流的 PPARγ 乙酰化抑制剂，提高胰岛素增敏效力、安全性和 因此，这项研究的完成将为进一步的临床开发做好准备，以减少副作用。 当前胰岛素抵抗和 T2D 的流行。