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: 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
• 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

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.

项目概要 IKKbeta 的激活与炎症有关，并且在小鼠模型中加速 在癌基因存在或抑癌基因缺失的情况下发生肿瘤。四种 IKKbeta 抑制剂 进入临床试验，但由于安全性不佳、缺乏疗效或没有获得 FDA 批准 投资组合重新定位。 MAP3K1 是一种磷酸化 IKKb 的上游激酶，较高的 MAP3K1 水平 与胰腺癌患者较差的 5 年生存率相关，使其成为有吸引力的治疗靶点。 我们最近报道了一种 MAP3K1 抑制剂 (IKAM-1) 的发现，它可以降低 p-IKKb 水平，减少肿瘤 Krasmutation 驱动的胰腺癌的生长和转移。结构引导修饰验证 IKAM-1 结合模式并确定2为改进的抑制剂。具有 12 个蛋白水解靶向嵌合体 (PROTAC) 目前正在进行临床试验，PROTAC 正迅速成为药物发现的主流方法。合成 使用 2 作为头组对一组重点 PROTAC 进行评估，结果确定了 50-008 在 269 种癌细胞系中表现出广泛的抗癌活性，IC50 < 100 nM。在此应用中，我们建议， (a) 进行 RNA-seq 和全蛋白质组筛选以阐明作用机制，(b) 优化 通过优化接头构象来提高功效，并 (c) 评估 50-008 或类器官中的改进类似物 和肿瘤模型。这些研究将确定具有明确 MOA 且适合 IND 毒性的主要候选药物 研究。