Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

 描述（由申请人提供）：Kras突变与约30%的癌症患者和约90%的胰腺导管腺癌（PDAC）患者相关。 Kras突变激活多种信号级联以驱动肿瘤发生。 动物模型的出现，忠实地概括了疾病的病理及其进展，导致更好地了解Kras突变驱动的肿瘤发生。 在这些信号级联中的蛋白质的遗传和药理学操纵已经导致了治疗干预的潜在靶点的鉴定。 例如，KrasG 12 D突变体在小鼠中的胰腺特异性表达导致PDAC，然而，当IKKβ在上述模型中同时失活时，没有小鼠发生PDAC。 这暗示IKKβ是Kras突变驱动的癌症治疗干预的潜在靶点。 近年来，医药行业开发了多种小分子IKKβ抑制剂，用于治疗慢性炎症性疾病。 几乎所有开发的IKKβ抑制剂都是ATP竞争性的。 尽管对许多候选药物进行了完整的临床前表征，但迄今为止FDA尚未批准任何一种药物用于临床。 这是因为ATP竞争性IKKβ抑制剂在动物中表现出与靶点活性相关的毒性。 我们最近发现了一种非ATP竞争性IKKβ抑制剂，其毒性特征与ATP竞争性IKKβ抑制剂不同。 此外，在原位胰腺肿瘤模型中，与载体对照相比，用我们的抑制剂治疗的小鼠显示出减少的肿瘤生长和转移。 在套细胞淋巴瘤模型中，与溶剂处理的小鼠相比，用我们的抑制剂处理的小鼠的中位存活率几乎翻了一番。 基于本申请中的这些研究，我们假设非ATP竞争性IKKβ抑制剂是Kras突变驱动的癌症的可行治疗剂。 我们的长期目标是通过优化我们的非ATP竞争性IKKβ抑制剂，开发IND毒性研究的主要候选药物。 为了实现这一目标，在目标1中，我们将通过对IKKβ进行生物物理学和X射线晶体学研究，阐明非ATP竞争性IKKβ抑制剂的作用机制。 在目标2中，我们计划进行结构引导的命中-先导优化，以鉴定具有改进的药物样性质的类似物，其适合于临床前开发。 在目标3中，我们将在遗传和原位胰腺癌模型中评估最佳抑制剂与当前标准治疗的组合。

 DESCRIPTION (provided by applicant): Mutations in Kras are associated with ~30% of all cancer patients and ~90% of pancreatic ductal adenocarcinoma (PDAC) patients. The gain of function Kras mutations activate a variety of signaling cascades to drive tumorigenesis. The emergence of animal models that faithfully recapitulate the pathology of the disease and its progression has led to a better understanding of Kras mutation driven tumorigenesis. Genetic and pharmacological manipulation of proteins in these signaling cascades has led to the identification of potential targets for therapeutic intervention. For example, pancreas specific expression of KrasG12D mutant in mice leads to PDAC, however none of the mice developed PDAC when IKKβ was concurrently inactivated in the above model. This implicates IKKβ as a potential target for therapeutic intervention for Kras mutation driven cancers. Several small molecule IKKβ inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Nearly all IKKβ inhibitors developed were ATP-competitive. Despite complete preclinical characterization of many candidates, to date FDA has approved none of them for clinical use. This is because the ATP competitive IKKβ inhibitors exhibited on target of site activity associated toxicity in animals. We recently discovered a non-ATP competitive IKKβ inhibitor that does not share the toxicity profile observed with ATP competitive IKKβ inhibitors. Moreover in an orthotopic pancreatic tumor model, mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. The median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice in a mantle cell lymphoma model. Based on these studies in this application we hypothesize that non-ATP competitive IKKβ inhibitors are viable therapeutics for Kras mutation driven cancers. Our long-term goal is to develop a lead candidate for IND enabling toxicity studies by optimizing our non-ATP competitive IKKβ inhibitor. Towards this goal, in aim 1, we will elucidate the mechanism of action of the non-ATP competitive IKKβ inhibitor by conducting biophysical and x-ray crystallography studies with IKKβ. In aim 2, we plan to conduct a structure guided hit-to-lead optimization to identify analogs with improved drug- like properties that are suitable for preclinical development. In aim 3, we will evaluate the best inhibitor in combination with the current standard of care in genetic and orthotopic pancreatic cancer models.