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该疾病的一个特征，其特征是无法对正常循环水平的胰岛素做出反应，并且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。我们假设，诱导NFκB下游的抗炎程序在保持能量储存、减少能量消耗和确保肥胖期间胰岛素抵抗的维持中起关键作用。为此，我们寻找了非典型IKK的TBK1和ikk御柱的抑制剂，并计划开发这些作为新的治疗方式。我们将有三个目标：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lexanox的类似物，其效力和代谢稳定性更高；2)在肥胖型2型糖尿病小鼠模型中，我们将开发新的ikkλ和TBK1抑制剂，这些抑制剂代表着新的化学实体，其效力、药物特性和体内活性都得到了提高；3)为了支持这些新化合物的临床开发，我们将开发ikk御柱/TBK1抑制的体内生物标志物。

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.