Targeting Diabetes With Novel SERCA Allosteric Activators

肥胖和胰岛素抵抗是2型糖尿病的主要原因， 给全世界社会带来健康负担。与糖尿病相关的主要扰动是 钙稳态和底物代谢异常，以及胰岛素诱导 阻力有趣的是，内质网（ER）Ca 2+水平的破坏主要引起 由于肌浆网/内质网Ca 2 +-ATP酶（SERCA）功能受损， 证实可触发肝脏和β细胞中的ER应激，导致胰岛素的产生 抵抗肥胖和糖尿病。因此，靶向功能失调的SERCA 2将 减轻糖尿病中异常的ER应激和相关疾病。我们 在胰岛素抵抗和2型糖尿病的遗传模型（ob/ob小鼠）中激活SERCA 2b 用一类新型的小分子来激活SERCA酶并拯救ER， 应激诱导的细胞死亡这些化合物适合于优化效力，并且 在治疗糖尿病方面有巨大的潜力。对糖尿病动物模型的研究表明， 显著改善葡萄糖耐量、肝脂肪变性和代谢，以及 保持β细胞功能和存活。通过药物化学和类比 战略，我们的目的是在这个建议进行复合优化这些新的系列， SERCA激活剂，并在体外和体内对其进行更广泛的分析，以进一步开发 作为基于SERCA的治疗方式来治疗糖尿病及其并发症。

Obesity and insulin resistance are major causes of type 2 diabetes, representing an enormous health burden to societies worldwide. 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 caused primarily by impaired function of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been demonstrated to trigger ER stress in liver and β cell leading to the development of insulin resistance in obesity and diabetes conditions. Thus, targeting dysfunctional SERCA2 will alleviate aberrant ER stress and associated disorders in diabetes. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel class of small molecules that allosterically activate SERCA enzyme and rescue ER stress-induced cell death. These compounds are amenable to optimization for potency, and have enormous potential to treat diabetes. Studies in animal models of diabetes show significant improvement in glucose tolerance, hepatic steatosis and metabolism, and preservation of β-cell function and survival. Through medicinal chemistry and analoging strategies, we aim in this proposal to conduct compound optimization of these novel series of SERCA activators and profile them more extensively in vitro and in vivo for further development as SERCA-based therapeutic modalities to treat diabetes and its complications.