Molecular Characterization of Novel Insulin Sensitizers

新型胰岛素敏化剂的分子表征

• 批准号: 8986841
• 负责人: Patrick Robert Griffin
• 金额: $ 60.57万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986841
• 关键词: AF2; Address; Adverse effects; Affinity; Age; Agonist; Animal Model; Binding; Biology; Blood Plasma Volume; Cardiomegaly; Cause of Death; Cell model; ChIP-seq; Chemicals; Complex; Coupled; Crystallography; DNA; Deuterium; Development; Diabetes Mellitus; Diet; Edema; Fracture; Gene Expression; Gene Targeting; Generic Drugs; Genes; Genomics; Health; Heart failure; Hemodilution; Human; Hydrogen; Incidence; Insulin; Ligands; Link; Malignant neoplasm of urinary bladder; Mediating; Metabolic Diseases; Molecular; Molecular Conformation; Mus; Mutagenesis; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral Administration; Outcome Study; PPARG gene; Pharmaceutical Preparations; Phosphorylation; Physiological; Pioglitazone; Population; Property; Proteins; Proteomics; RXR; Recruitment Activity; Repression; Research; Risk; Rodent Model; Safety; Signal Pathway; Structure-Activity Relationship; Technology; Testing; Therapeutic Index; Tissues; Translations; Treatment Efficacy; United States National Center for Health Statistics; Weight Gain; analog; bone; bone mass; bone quality; cancer risk; diabetic; improved; in vivo; insight; insulin sensitizing drugs; man; novel; pre-clinical; promoter; public health relevance; receptor; response; structural biology

 DESCRIPTION (provided by applicant): The incidence of diabetes is increasing rapidly as the percentage of the population ages and becomes more obese. According to the National Center for Health Statistics diabetes is now the seventh leading cause of death in the US. The approach for first-line treatment of type 2 diabetes mellitus (T2DM) has moved away from the use of the TZD class of insulin sensitizers as safety concerns over their use have grown. This is unfortunate as TZDs have consistently shown robust insulin sensitization efficacy for treatment of T2DM. While weight gain is associated with use of TZDs, the major safety concerns include edema, plasma volume expansion (PVE/hemodilution) which is linked to cardiomegaly and heart failure, increased risk of bone fractures and specific to pioglitazone, increased risk in bladder cancer. Studies in animal models and in man have shown that indicators of weight gain and PVE, while not eliminated, can be minimized without loss of insulin sensitization by the use of partial agonists of PPARG (minimal agonism of the receptor as compared to TZDs regardless of concentration of compound). While it is unclear if the bone fracture risk can be minimized with use of such agents, these studies clearly demonstrate that insulin sensitization afforded by PPARG ligands does not correlate with the level of classical agonism they induce (AF2-mediated agonism). We demonstrated that the insulin sensitization afforded by partial agonist and TZD treatment correlates with the ability of these drugs to block the obesity-induced phosphorylation of PPARG at S273 (pS273). In 2011, we showed that the PPARG ligand SR1664 does not induce classical agonism yet potently blocks pS273, and is efficacious as an insulin sensitizer in rodent models of diabetes. Recently, we have made significant advances on the drug-like properties of SR1664 resulting in compounds such as SR11023 and SR10171 that demonstrate efficacy in obese mice following once-a-day oral administration. These compounds represent a significant advancement towards developing PPARG modulators with an improved therapeutic index; however, several questions remain; 1) how does pS273 of PPARG repress genes linked with obesity and diabetes, and what other PTMs are involved? We anticipate that factors are recruited to or displaced from the PPARG complex in response to pS273 and these factors influence expression of a subset of target genes. Thus, when ligands block pS273, the interaction of these factors with the complex is altered. We will determine what these factors are and if they contribute to the mechanism of action of our novel compounds; 2) what are the structural determinants that facilitate the action of SR11023 and SR10171. We will use proven technologies to answer this; and 3) will the lack of classical agonism fully dissociate efficacy from the major side effects of PPARG modulators, particularly their effects on bone? Here we will use chemical and structural biology with appropriate cell and animal models coupled with comprehensive proteomic and genomic analysis to address these questions. The proposed research will provide insight into the molecular components of the PPARG signaling pathway, structural determinants for generating high affinity non-agonist ligands that block pS273, and a better understanding of the impact of modulating PPARG on bone. While pioglitazone will become generic soon, its association with bladder cancer risk and its negative effects on bone will ultimately limit its use. Therefore, a significant need exists for a safer yet efficacious inslin sensitizer for treatment of T2DM.

 描述（由申请人提供）：糖尿病的发病率随着人口老龄化和肥胖程度的增加而迅速增加。根据国家健康统计中心的数据，糖尿病现在是美国第七大死亡原因。2型糖尿病（T2 DM）的一线治疗方法已不再使用TZD类胰岛素增敏剂，因为其使用的安全性问题越来越多。这是不幸的，因为TZD在治疗T2 DM方面一直显示出稳健的胰岛素增敏疗效。虽然体重增加与TZD的使用相关，但主要的安全性问题包括水肿、与心脏肥大和心力衰竭相关的血浆容量扩张（PVE/血液稀释）、骨折风险增加和吡格列酮特有的膀胱癌风险增加。在动物模型和人体中的研究表明，通过使用PPARG的部分激动剂（与TZD相比，无论化合物的浓度如何，受体的激动作用最小），体重增加和PVE的指标虽然没有消除，但可以最小化而不损失胰岛素敏化作用。虽然尚不清楚使用这些药物是否可以使骨折风险最小化，但这些研究清楚地表明，PPARG配体提供的胰岛素致敏作用与它们诱导的经典激动作用（AF 2介导的激动作用）水平无关。我们证明了部分激动剂和TZD治疗所提供的胰岛素增敏作用与这些药物阻断肥胖诱导的PPARG在S273（pS273）处磷酸化的能力相关。在2011年，我们显示PPARG配体SR 1664不诱导经典激动作用，但有效地阻断pS273，并且在糖尿病的啮齿动物模型中作为胰岛素增敏剂是有效的。最近，我们在SR 1664的药物样性质方面取得了重大进展，产生了SR 11023和SR 10171等化合物，这些化合物在肥胖小鼠中每天一次口服给药后显示出疗效。这些化合物代表了开发具有改善的治疗指数的PPARG调节剂的重大进展;然而，仍存在几个问题：1）PPARG的pS273如何抑制与肥胖和糖尿病相关的基因，以及涉及哪些其他PTM？我们预计，因子被募集到PPARG复合物中或从PPARG复合物中置换以响应pS273，并且这些因子影响靶基因的子集的表达。因此，当配体阻断pS273时，这些因子与复合物的相互作用被改变。我们将确定这些因素是什么，以及它们是否有助于我们的新型化合物的作用机制; 2）促进SR 11023和SR 10171作用的结构决定因素是什么。我们将使用成熟的技术来回答这个问题; 3）缺乏经典的激动作用是否会使PPARG调节剂的主要副作用，特别是它们对骨的作用完全分离？在这里，我们将使用化学和结构生物学与适当的细胞和动物模型，结合全面的蛋白质组学和基因组学分析来解决这些问题。拟议的研究将深入了解PPARG信号通路的分子组成，产生阻断pS273的高亲和力非激动剂配体的结构决定因素，以及更好地了解调节PPARG对骨的影响。虽然吡格列酮将很快成为通用药物，但其与膀胱癌风险的相关性及其对骨骼的负面影响将最终限制其使用。因此，存在对更安全但有效的胰岛素增敏剂用于治疗T2 DM的显著需求。