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: 10430186
• 负责人: Li Qiang
• 金额: $ 46.25万
• 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/10430186
• 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 alpha; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Prevalence; Prevention; Property; Reporting; Research; SIRT1 gene; Safety; Standardization; Structure; Structure-Activity Relationship; Sum; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Validation; Water; Weight Gain; Work; absorption; analog; base; bone; bone loss; clinical development; comorbidity; cost; design; diaries; diet-induced obesity; driving force; drug discovery; 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; pre-clinical; prototype; 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.

项目摘要 该建议旨在利用跨学科领域的基本发现来开发一种新颖且安全的治疗 对于大流行2型糖尿病（T2D）。肥胖连接胰岛素抵抗是T2D和其他的关键驱动力 代谢障碍。尽管广泛使用常用的抗糖尿病药物进行T2D治疗，但 在美国，T2D的患病率继续飙升，每年成本超过3000亿美元。转录因子 过氧化物体增殖物激活受体γ（PPARγ）是胰岛素的重要治疗靶标 敏感性及其全部激动剂TZD药物是迄今为止最有效的胰岛素敏感药物。但是，TZD 药物与不良副作用有关，包括心力衰竭和体重增加，因为TZD诱导了 PPARγ的激动剂不仅激活了负责胰岛素敏化的基因的表达，而且还激活 那些与副作用相关的基因，从而严重阻碍了TZD的临床使用。最近的研究 已经表明PPARγ后翻译后修饰（PTM）可能导致选择性激活 PPARγ靶基因导致对胰岛素对TZD敏化的有益作用的脱钩 相关的不利影响。我们的团队最近发现，通过K268的脱乙酰基化和PPARγ中的K293脱乙酰化。 NAD+依赖性脱乙酰基酶SIRT1在这种脱钩中起关键作用。令人兴奋的是，PIS发展了 与PPARγ结合的新型PPARγ激动剂TPMD特异性抑制PPAR乙酰化。重要的是， TPMD提高了胰岛素敏感性，并增加了白色到棕色的脂肪细胞转化（褐变）和能量 在遗传和日记肥胖小鼠模型中不引起TZD相关的副作用而不会引起TZD相关的支出。在这个 应用，由两个PI领导的团队在糖尿病药物发现和PPARγ方面具有完整的专业知识 生物学将使用TPMD作为起始分子，以识别PPARγ乙酰化的第一类抑制剂 发挥潜在的胰岛素敏感性和褐变活性，以及​​更好的安全性和药代动力学（PK）特性。 在AIM 1中，他们将通过迭代和平行的医学化学采用基于结构的设计来识别 TPMD类似物具有抑制PPARγ乙酰化的效力。在AIM 2中，铅类似物将是 继续进行标准化的体外ADMET分析和体内药代动力学研究以选择这些 具有最有利的药物特性。在AIM 3中，将严格测试铅候选人 它们在肥胖和遗传小鼠模型中的体内效率和安全性。 PI将采用其“标准化” 代谢特征和与TZD相关的不良副作用的评估。拟议的研究将 产生一流的PPARγ乙酰化抑制剂，可提高胰岛素敏感性，安全性和 PK配置文件。这项研究的完整性将得到充分的精力，以进一步临床开发，以减少 胰岛素抵抗和T2D的当前发作。