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：
10731443
负责人：
Amarnath Natarajan
金额：
$ 38.38万
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 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731443
关键词：
Acceleration Apoptosis BRAF gene Binding Biological Availability Body Weight Breast Cancer cell line Cell Cycle Cell Line Cell Membrane Permeability Clinical Data Clinical Trials Collaborations Colonic Neoplasms Complication Cullin Proteins Development Dose Dose Limiting Drug Kinetics Evaluation Exhibits FDA approved Foundations Growth Head Inflammation Inhibition of Cancer Cell Growth Interleukin-6 Invaded Investigation Lead Ligase Lung MAP3K1 gene MEKs Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Metabolic Modeling Modification Molecular Conformation Mus Mutation Nature Neoplasm Metastasis Oncogenes Oral Organoids Pancreas Paper Peripheral Permeability Pharmacodynamics Phosphorylation Positioning Attribute Protac Proteome Publishing Quinoxalines Reporting Resistance Safety Signal Transduction Solubility Structure Study models Surface T47D Testing Thalidomide Toxic effect Tumor Suppressor Genes United States National Institutes of Health Western Blotting Xenograft procedure analog anticancer activity drug discovery early onset efficacy evaluation flexibility improved inhibitor intraperitoneal lead candidate lead optimization migration mouse model novel therapeutics pancreatic cancer model pancreatic cancer patients pancreatic neoplasm predictive modeling screening small molecule inhibitor therapeutic target transcriptome sequencing tumor tumor growth tumorigenesis upstream kinase

项目摘要

Project Summary Activation of IKKbeta has been implicated in inflammation and in mouse models accelerates tumorigenesis in the presence of an oncogene or the loss of tumor suppressor gene. Four IKKbeta inhibitors entered clinical trials however none were FDA approved due to unfavorable safety profile, lack of efficacy or portfolio repositioning. MAP3K1 is an upstream kinase that phosphorylates IKKb and higher MAP3K1 levels is associated with poorer 5-year survival in pancreatic cancer patients, making it an attractive therapeutic target. We recently reported the discovery of a MAP3K1 inhibitor (IKAM-1) that reduced p-IKKb levels, reduced tumor growth and metastasis in Krasmutation driven pancreatic cancer. Structure-guided modification validated IKAM-1 binding mode and identified 2 as an improved inhibitor. With 12 proteolysis targeting chimeras (PROTACs) currently in clinical trials PROTACs are rapidly emerging as a mainstream approach in drug discovery. Synthesis and evaluation of a focused set of PROTACs using 2 as the head group led to the identification of 50-008 that exhibited broad anticancer activities with IC50 < 100 nM in 269 cancer cell lines. In this application we propose, to (a) conduct RNA-seq and proteome-wide screens to elucidate the mechanism of action, (b) optimize for efficacy through optimization of linker conformation and (c) evaluate 50-008 or an improved analog in organoids and tumor models. These studies will identify a lead candidate with defined MOA suitable for IND enabling toxicity studies.

项目摘要 Ikkbeta的激活与炎症和小鼠模型有关在癌基因存在或肿瘤抑制基因丧失的情况下，肿瘤发生。四个ikkbeta抑制剂进入临床试验，但是由于安全性不佳，缺乏功效或投资组合重新定位。 MAP3K1是一种上游激酶，磷酸化IKKB，更高的Map3k1级别为与胰腺癌患者的5年生存率较差有关，使其成为有吸引力的治疗靶点。我们最近报道了发现MAP3K1抑制剂（IKAM-1）的发现，该抑制剂降低了P-IKKB水平，肿瘤降低典型驱动胰腺癌的生长和转移。结构引导的修改验证了IKAM-1 结合模式并确定2是改进的抑制剂。与12个蛋白水解靶向嵌合体（Protac）目前，在临床试验中，Protac迅速成为药物发现中的主流方法。合成并使用2作为头组评估一组专注的Protac，导致50-008的识别在269个癌细胞系中具有IC50 <100 nm的广泛抗癌活性。在此应用程序中，我们建议到（a）进行RNA-seq和全蛋白质组屏幕以阐明作用机理，（b）优化通过优化接头构象和（c）评估50-008的功效或类似器中的改进类似物和肿瘤模型。这些研究将确定具有适用于IND毒性的定义MOA的主要候选者研究。