Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

基于喹喔啉的 IKKbeta 抑制剂的开发，用于治疗 Kras 驱动的癌症

• 批准号: 9271163
• 负责人: Amarnath Natarajan
• 金额: $ 34.41万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-09 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271163
• 关键词: Animal Model; Animals; Binding; Binding Sites; Bioavailable; Biological Assay; Biophysics; CASP1 gene; Cancer Model; Cancer Patient; Cell Line; Cells; Cessation of life; Chronic; Clinical; Crystallization; Development; Disease; Drug Industry; Drug Kinetics; Drug or chemical Tissue Distribution; Exhibits; Follow-Up Studies; Generations; Genetic; Genetic Transcription; Goals; Growth; Half-Life; Infection; Inflammatory; Inhibition of Apoptosis; Interleukin-1 beta; Intervention; Kinetics; Knock-out; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of pancreas; Mantle Cell Lymphoma; Mass Spectrum Analysis; Mediating; Modeling; Modification; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Oral; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phosphotransferases; Plasminogen Activator Inhibitor 2; Predisposition; Process; Property; Proteins; Quinoxalines; Rest; Serum; Signal Transduction; Site; Stimulus; Structure; Structure-Activity Relationship; Survival Rate; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Urea; X-Ray Crystallography; analog; base; comparative efficacy; crosslink; design; drug metabolism; extracellular; gain of function; gemcitabine; genetic manipulation; improved; inhibitor/antagonist; interest; interleukin-1beta-converting enzyme inhibitor; macrophage; member; mutant; mutant mouse model; pancreas xenograft; pancreatic cancer cells; pancreatic neoplasm; personalized medicine; pre-clinical; preclinical development; prevent; public health relevance; response; screening; small molecule; standard of care; targeted cancer therapy; targeted treatment; therapeutic target; tumor; tumor growth; tumorigenesis

 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.

 描述(申请人提供)：Kras基因突变与约30%的癌症患者和~90%的胰腺导管腺癌(PDAC)患者相关。Kras功能突变的获得激活了各种信号级联反应，从而推动肿瘤的发生。动物模型的出现忠实地概括了疾病的病理及其进展，使人们更好地理解了Kras突变驱动的肿瘤发生。对这些信号级联中的蛋白质进行遗传和药物操作，已经导致了治疗干预的潜在靶点的确定。例如，在上述模型中，KrasG12D突变体在小鼠胰腺中的特异性表达导致了PDAC，但在上述模型中，当IKKβ同时失活时，小鼠均未发生PDAC。这意味着IKKβ是治疗kras突变导致的癌症的潜在靶点。制药行业开发了几种小分子IKKβ抑制剂，用于治疗慢性炎症性疾病。几乎所有开发的IKKATP抑制剂都是β竞争性的。尽管许多候选药物具有完整的临床前特征，但到目前为止，FDA还没有批准任何一种药物用于临床。这是因为三磷酸腺苷竞争性IKKβ抑制剂在动物体内表现出靶点活性相关的毒性。我们最近发现了一种非三磷酸腺苷竞争性IKKβ抑制剂，与观察到的三磷酸腺苷竞争性IKKβ抑制剂的毒性特征不同。 此外，在原位胰腺肿瘤模型中，与赋形剂对照组相比，使用我们的抑制剂治疗的小鼠显示出肿瘤生长和转移减少。在套细胞淋巴瘤模型中，与赋形剂治疗的小鼠相比，使用我们的抑制剂治疗的小鼠的中位存活率几乎翻了一番。基于本应用中的这些研究，我们假设非三磷酸腺苷竞争性IKKβ抑制剂是治疗Kras突变驱动的癌症的可行疗法。我们的长期目标是通过优化我们的非三磷酸腺苷竞争性IKKβ抑制剂，开发一种用于IND启用毒性研究的领先候选药物。为此，在目标1中，我们将通过对IKKβ进行生物物理和X射线结晶学研究，阐明非三磷酸腺苷竞争性IKKβ抑制剂的作用机制。在目标2中，我们计划进行结构指导的Hit-to-Lead优化，以确定具有改进的类药物特性的类似物，这些类似物适合临床前开发。在目标3中，我们将结合目前在遗传性和原位胰腺癌模型中的护理标准来评估最佳的抑制剂。