Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

项目摘要 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 大流行性2型糖尿病（T2 D）。肥胖相关的胰岛素抵抗是T2 D和其他疾病的关键驱动力。 代谢紊乱尽管广泛使用常用的抗糖尿病药物治疗T2 D， 在美国，T2 D的患病率继续飙升，每年的成本超过3000亿美元。转录因子 过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPARγ）是胰岛素治疗的重要靶点 致敏剂及其完全激动剂TZD药物是迄今为止最有效的胰岛素致敏药物。然而，TZD 药物与心力衰竭和体重增加等不良副作用有关，因为TZD引起的饱腹感 PPARγ的激动作用不仅激活负责胰岛素增敏的基因的表达， 这些基因与副作用相关，从而严重阻碍了TZD的临床应用。最近的研究 已经表明，PPARγ翻译后修饰（PTM）可能导致选择性激活 导致胰岛素增敏的有益作用与TZD脱钩的PPARγ靶基因- 相关的不良影响。我们的研究小组最近发现，在过氧化物酶体增殖物激活受体γ中的K268和K293处的去乙酰化， NAD+依赖性脱乙酰酶SirT 1在这种解耦中起关键作用。令人兴奋的是，PI已经开发了一个 新型的PPARγ激动剂TPMD，其结合到PPARγ上以特异性地抑制PPAR γ乙酰化。重要的是， TPMD改善胰岛素敏感性，增加白色至棕色脂肪细胞转化（布朗宁）和能量 在遗传性肥胖和乳型肥胖小鼠模型中，这两种方法都可以减少TZD消耗而不引起TZD相关的副作用。在这 申请，由两名PI领导的团队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，以鉴定第一类PPARγ乙酰化抑制剂， 发挥有效的胰岛素增敏和布朗宁活性以及更好的安全性和药代动力学（PK）性质。 在目标1中，他们将采用基于结构的设计，通过迭代和平行的药物化学来识别 TPMD类似物具有改善的抑制PPARγ乙酰化的效力。在目标2中，电极导线类似物将 进行标准化核心体外ADMET试验和体内药代动力学研究，以选择那些 具有最有利的药理学特性。在目标3中，主要候选人将接受严格的测试， 它们在肥胖症和遗传小鼠模型中的体内功效和安全性。PI将采用其“标准化” 代谢特征和TZD相关不良副作用的评估。拟议的研究将 生产一流的PPARγ乙酰化抑制剂，具有改善的胰岛素增敏效力，安全性， PK特征。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 胰岛素抵抗和2型糖尿病的流行。

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.