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，对 给全世界的社会带来健康负担。与糖尿病相关的主要干扰因素有 钙稳态和底物代谢异常与胰岛素的诱导 抵抗。有趣的是，内质网(ER)钙离子水平的紊乱主要是由于 由于肌浆网/内质网功能受损，钙-三磷酸腺苷酶(SERCA) 已证实在肝脏和β细胞中触发内质网应激导致胰岛素的形成 对肥胖和糖尿病的抵抗力。因此，靶向功能失调的SERCA2将 减轻糖尿病患者异常的内质网应激和相关疾病。我们从药理上讲 胰岛素抵抗和2型糖尿病遗传模型中SERCA2b的激活(ob/ob小鼠) 用一类新的小分子变构激活SERCA酶和拯救ER 应激诱导的细胞死亡。这些化合物可以进行效力优化，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 显著改善糖耐量、肝脏脂肪变性和代谢，以及 保存β细胞的功能和存活。通过药物化学和类比 策略，我们在这项建议中的目的是对这些新颖的系列进行复合优化 SERCA激活剂及其在体外和体内更广泛的分布，以便进一步开发 作为以SERCA为基础的治疗糖尿病及其并发症的方法。

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.