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.

项目总结 这项建议旨在利用跨学科领域的基本发现来开发一种新的、更安全的疗法。 用于大流行性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 代谢紊乱。尽管常用的抗糖尿病药物广泛用于T2D治疗，但 T2D的流行率继续飙升，在美国每年的成本超过3000亿美元。转录因子 过氧化体增殖物激活受体γ(PPARγ)是胰岛素治疗的重要靶点 增敏及其完全激动剂TZD药物是迄今为止最有效的胰岛素增敏药物。然而，TZD 药物与副作用有关，包括心力衰竭和体重增加，因为TZD诱导的完全 PPARγ激动剂不仅能激活胰岛素增敏相关基因的表达，还能激活 这些基因与副作用有关，从而严重阻碍了TZDS的临床应用。最新研究 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TZD对胰岛素增敏的有益作用解偶联- 相关不良反应。我们的团队最近发现PPARγ中K268和K293位的脱乙酰基是由 依赖于NAD+的脱乙酰酶SirT1在这种解偶联过程中起着关键作用。令人兴奋的是，私家侦探已经开发出一种 一种新型的PPARγ激动剂TPMD，它与PPARγ结合，特异性地抑制PPAR的乙酰化。重要的是 TPMD改善了胰岛素敏感性，增加了脂肪细胞从白色到棕色的转化(褐变)和能量 在遗传性和乳房性肥胖小鼠模型中，在不引起与TZD相关的副作用的情况下，这些药物的使用成本很低。在这 应用，由两个在糖尿病药物发现和PPARγ方面具有互补专业知识的PI领导的团队 生物将使用TPMD作为起始分子来鉴定PPARγ乙酰化的一流抑制剂 具有强大的胰岛素增敏和褐变活性，并具有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确定 TPMD类似物具有更强的抑制PPARγ乙酰化的效力。在目标2中，铅的类似物将是 进行标准化核心体外ADMET测定和体内药代动力学研究，筛选出 具有最好的药理作用。在目标3中，主要候选人将接受严格的测试 它们在肥胖和遗传小鼠模型中的体内有效性和安全性。私人投资总监将采用他们的“标准化” TZD相关不良反应的代谢特征和评估。拟议的研究将 生产一流的PPARγ乙酰化抑制剂，提高了胰岛素增敏效力、安全性和 PK配置文件。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 目前流行的胰岛素抵抗和T2D。