IKKepsilon/TBK1 Inhibitors for the Treatment of Obesity and Type 2 Diabetes

描述(由申请人提供)：毫无疑问，我们正处于糖尿病的全球流行之中。胰岛素抵抗被认为是这种疾病的一个特征，定义为无法对正常的循环胰岛素水平做出反应，通常与肥胖密切相关。最近的数据表明，肥胖和胰岛素抵抗之间存在炎症联系。我们推测，诱导NFκB下游的抗炎程序在保存能量储存、减少能量消耗和确保在肥胖期间维持胰岛素抵抗方面起着关键作用。为此，我们已经寻找了非典型性IKK的Tbk1和IKKϵ的抑制剂，并计划将其开发为新的治疗方法。我们将实施这一计划，目标有三：1)我们将利用药物化学和基于结构的设计方法，开发新发现的抑制剂氨来昔诺的类似物，提高其效力和代谢稳定性；2)我们将开发代表新的化学实体的新型IKKϵ和Tbk1抑制剂，其驱动因素是药效提高、药效改善以及在小鼠肥胖2型糖尿病模型中的体内活性；3)为了支持这些新化合物的临床开发，我们将开发体内抑制IKKϵ/Tbk1的生物标记物。

DESCRIPTION (provided by applicant): There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin, and is usuall closely associated with obesity. Recent data suggest an inflammatory link between obesity and insulin resistance. We hypothesize that the induction of a counter-inflammatory program downstream of NFκB plays a key role in preserving energy storage, reducing energy expenditure and ensuring that insulin resistance is maintained during obesity. To this end, we have searched for inhibitors of the noncanonical IKK's TBK1 and IKKϵ, and plan to develop these as new therapeutic modalities. We will pursue this plan with three aims: 1) We will development analogs of the newly discovered inhibitor amlexanox with increased potency and metabolic stability, using both medicinal chemistry and structure- based design approaches; 2) We will develop novel inhibitors of IKKϵ and TBK1 that represent new chemical entities, driven by increased potency, improved pharmaceutical properties and in vivo activity in mouse models of obese type 2 diabetes; and 3) In order to support the clinical development of these new compounds, we will develop in vivo biomarkers for IKKϵ/TBK1 inhibition.