Targeting Diabetes With Novel Small Molecule Therapeutics

 描述（由申请人提供）：肥胖和胰岛素抵抗是2型糖尿病的主要原因，2型糖尿病对全世界社会造成巨大的健康负担，是大多数发达国家的第四大死亡原因。与糖尿病相关的主要扰动是钙稳态和底物代谢的异常，以及胰岛素抵抗的诱导。有趣的是，内质网（ER）Ca 2+水平的破坏已被证明触发ER应激，导致肥胖和糖尿病疾病中胰岛素抵抗的发展。内质网应激的一个主要原因是肌浆网/内质网Ca ~（2+）-ATP酶（SERCA）功能失调引起的钙稳态紊乱。事实上，SERCA 2b活性和表达在肥胖/糖尿病动物模型中减少。通过短期基因转移上调肥胖和糖尿病小鼠肝脏中的SERCA，降低ER应激并改善葡萄糖稳态。因此，靶向功能失调的SERCA 2 β将减轻糖尿病中的异常ER应激和相关病症。使用新的筛选方法，我们发现了一系列新的药物样小分子，它们激活SERCA并挽救ER应激诱导的细胞死亡，易于优化效力，并具有治疗糖尿病的巨大潜力。在糖尿病动物模型中的初步结果显示葡萄糖耐量、胰岛素敏感性、肝脂肪变性和代谢的显著改善。在该提案中，我们的目标是对我们的新型别构SERCA激活剂系列进行化合物优化，并更广泛地对其进行分析，以观察其在体内糖尿病模型中的功效，并证明这些新型SERCA激活剂拯救ER应激，改善葡萄糖耐量并恢复胰岛素敏感性。我们的目标是提供适合开发的药物样化合物作为治疗糖尿病的新治疗潜力。

 DESCRIPTION (provided by applicant): Obesity and insulin resistance are major causes of type 2 diabetes, which represents an enormous health burden to societies worldwide and is the fourth leading cause of death in most developed countries. Major perturbations associated with diabetes are abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels has been demonstrated to trigger ER stress leading to the development of insulin resistance in obesity and diabetes conditions. A major cause of ER stress is disturbed calcium homeostasis caused by dysfunctional sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). In fact, SERCA2b activity and expression is diminished in animal models of obesity/diabetes. Upregulation of SERCA in liver of obese and diabetic mice via short term gene transfer reduced ER stress and improved glucose homeostasis. Thus, targeting dysfunctional SERCA2 pharmacologically will alleviate aberrant ER stress and associated disorders in diabetes. Using novel screening methodology, we have discovered a series of novel, drug-like small molecules that activate SERCA and rescue ER stress-induced cell death, are amenable to optimization for potency, and have enormous potential to treat diabetes. Preliminary results in animal models of diabetes show significant improvement in glucose tolerance, insulin sensitivity, hepatic steatosis and metabolism. In this proposal, we aim to conduct compound optimization of our novel series of allosteric SERCA activators and profile them more extensively to observe efficacy in in vivo models of diabetes, and to demonstrate that these novel SERCA activators rescue ER stress, improve glucose tolerance and restore insulin sensitivity. Our goal is to provide drug-like compounds suitable for development as novel therapeutic potential to treat diabetes.