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

基本信息

批准号：
9102393
负责人：
Amarnath Natarajan
金额：
$ 35.56万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9102393
关键词：
Animal Model Animals Binding Binding Sites Bioavailable Biological Assay CASP1 gene Cancer Model Cancer Patient Cancer cell line Cells Cessation of life Chronic Clinical Crystallography 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 Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Plasminogen Activator Inhibitor 2 Predisposition Process Property Proteins Quinoxalines Rest Serum Signal Transduction Site Staging Stimulus Structure Structure-Activity Relationship Survival Rate Therapeutic Therapeutic Agents Therapeutic Intervention Toxic effect Urea Xenograft procedure 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 mouse model mutant mutant mouse model pancreatic cancer cells pancreatic neoplasm personalized medicine pre-clinical prevent public health relevance response screening small molecule standard of care targeted cancer therapy targeted treatment therapeutic target tumor tumor growth tumorigenesis

项目摘要

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（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 突变功能的获得会激活多种信号级联反应，从而驱动肿瘤发生。忠实地再现该疾病的病理学及其进展的动物模型使我们能够更好地了解 Kras 突变驱动的蛋白质的遗传和药理学操作。这些信号级联导致了治疗干预的潜在靶标的确定，例如，小鼠中 KrasG12D 突变体的胰腺特异性表达导致 PDAC，但是当 IKKβ 在上述模型中同时失活时，没有一只小鼠发生 PDAC。作为 Kras 突变驱动的癌症治疗干预的潜在靶点制药行业开发了几种小分子 IKKβ 抑制剂来治疗慢性炎症性疾病。 ATP 竞争性。尽管许多候选药物已完成临床前表征，但迄今为止 FDA 尚未批准它们用于临床，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。竞争性 IKKβ 抑制剂，与 ATP 竞争性 IKKβ 抑制剂观察到的毒性特征不同。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肿瘤生长和转移减少。与在套细胞淋巴瘤模型中用载体治疗的小鼠相比，用我们的抑制剂治疗的小鼠的中位生存率几乎翻倍。在此应用中的研究中，我们追求非 ATP 竞争性 IKKβ 抑制剂是 Kras 突变驱动的癌症的可行疗法。我们的长期目标是开发 IND 的主要候选药物，通过优化我们的非 ATP 竞争性来进行毒性研究。为了实现这一目标，在目标 1 中，我们将通过对 IKKβ 进行生物物理和 X 射线晶体学研究来阐明非 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命中。 - 进行先导优化，以确定具有改进的药物特性并适合临床前开发的类似物。在目标 3 中，我们将结合当前遗传和原位治疗标准来评估最佳抑制剂。胰腺癌模型。