Development of New Casein Kinase 1 Inhibitor for the Treatment of Brain Cancers

开发用于治疗脑癌的新型酪蛋白激酶 1 抑制剂

• 批准号: 9698320
• 负责人: Thomas D Bannister
• 金额: $ 71.43万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9698320
• 关键词: Adenocarcinoma Cell; Apoptosis; Binding Proteins; Biochemical; Biological; Biological Assay; Brain; Breast; Cell Adhesion Molecules; Cells; Clinical; Colorectal; Complement; Confocal Microscopy; Critical Pathways; Cytotoxic Chemotherapy; DNA Damage; DNA Repair; DNA Repair Gene; Development; Diffusion; Distant; Dose; Drug Kinetics; ERBB2 gene; Enzymes; Epithelial; Epithelial Cells; Epithelium; FDA approved; Failure; Florida; Fluorescence; Gene Expression Profiling; Genetic; Genetic Transcription; Genome; Glioblastoma; Glioma; Human; Image; Ionizing radiation; Lead; Liquid substance; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mammary Neoplasms; Matrix Metalloproteinases; Mesenchymal; Molecular Profiling; Mus; Nature; Neoplasm Metastasis; Oncogenic; P-Glycoprotein; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Protein Inhibition; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Publishing; Refractory; Regulation; Reporter; Research; Resistance; Role; Safety; Second Primary Cancers; Signal Transduction; Structure; Testing; Tumor Cell Invasion; Xenograft Model; advanced disease; analog; anti-cancer; anticancer activity; base; beta catenin; brain parenchyma; brain tissue; cancer cell; casein kinase; casein kinase I; cell killing; chemical property; chemotherapeutic agent; chemotherapy; design; drug metabolism; effective therapy; end stage disease; epithelial to mesenchymal transition; gene repair; improved; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel; outcome forecast; physical property; prevent; response; side effect; small molecule; small molecule inhibitor; stem-like cell; synergism; therapeutic evaluation; triple-negative invasive breast carcinoma; tumor; tumorigenesis; tumorigenic

High grade gliomas, especially glioblastoma (GBM), have exceptionally poor prognosis and cancers that metastasize to the brain, for example from the lung and breast are associated with advanced disease. Notably, our Multi-PI research team has discovered that casein kinase-1 delta and epsilon (CK1δ, CK1ε) are new therapeutic targets for GBM. This discovery originated from a small molecule screen by the Roush lab at Scripps Florida, who identified a class of highly potent and selective dual inhibitors of CK1δ and CK1ε. Further studies by the Duckett lab then showed that; (i) 11% of GBMs and 36% of all breast cancers have amplified CSNK1D; (ii) GBM and certain breast cancers including those that metastasize to the brain express elevated levels of CK1δ and Wnt/β-catenin transcription targets; (iii) brain metastatic lung adenocarcinoma cells that express CK1δ and CK1ε and are highly sensitive to our inhibitors; (iv) dual CK1δ/ε inhibitors induce rapid apoptosis of GBM, breast and lung cancer cells ex vivo, and tumor regression in vivo, but are not toxic to normal human epithelial cells and can be administered daily to mice long term without observable adverse side effects; (v) CK1δ/ε regulates expression of key factors involved in tumor cell invasion, (vi) CK1δ/ε regulates expression of essential DNA damage repair genes, and (vii) inhibition of CK1δ/ε augments the killing effects of IR, DNA damaging chemotherapeutic agents and PARP inhibitors. Collectively these findings support the premise that CK1δ is an exploitable target of GBM and other refractory cancers that metastasize to the brain. In Aim 1, using already established critical path assays, a validated research operating plan (ROP), an iterative medicinal chemistry approach based on a multi-parameter optimization strategy augmented by drug metabolism and pharmacokinetic studies, we will develop and deliver optimized dual and isoform selective brain penetrant CK1δ and CK1ε inhibitors. Efficacy and safety of these inhibitors will be tested in our intracranial human xenograft models in mice. In Aim 2, we will (i) identify the full cast of invasion related protein(s) modified by CK1δ activity, (ii) elucidate how CK1δ contributes to GBM tumor cell diffusion; (iii) determine how and at which stage CK1δ control aspects of the metastasis cascade from the periphery to the brain, and (iv) elucidate the role of CK1δ in regulating a glioma stem cell-like state. In Aim 3, we will determine; (i) the MOA of DNA damage- induced CK1δ-regulation of genome maintenance pathways in GBM, and (ii) define the safety margin associated with our lead CK1δ/ε inhibitor and the most efficacious combination for improved treatment in GBM.

高级别胶质瘤，尤其是胶质母细胞瘤（GBM），预后极差，并且是癌症 转移到大脑的肿瘤，例如从肺和乳房转移到大脑的肿瘤，与晚期相关 疾病。值得注意的是，我们的 Multi-PI 研究团队发现酪蛋白激酶 1 delta 和 epsilon （CK1δ、CK1ε）是 GBM 的新治疗靶点。这一发现源于一个小分子 佛罗里达州斯克里普斯的劳什实验室进行了筛选，他们鉴定出了一类高效且选择性的双重 CK1δ 和 CK1ε 抑制剂。达克特实验室的进一步研究表明： (i) 11% 的 GBM 36% 的乳腺癌有 CSNK1D 扩增； (ii) GBM 和某些乳腺癌，包括 那些转移到大脑的细胞表达升高水平的 CK1δ 和 Wnt/β-catenin 转录 目标； (iii) 表达 CK1δ 和 CK1ε 且高度表达的脑转移性肺腺癌细胞 对我们的抑制剂敏感； (iv)双重CK1δ/ε抑制剂诱导GBM、乳腺和肺的快速凋亡 离体癌细胞和体内肿瘤消退，但对正常人上皮细胞没有毒性 并且可以每天对小鼠长期给药，没有观察到的不良副作用； (v) CK1δ/ε 调节参与肿瘤细胞侵袭的关键因子的表达，(vi) CK1δ/ε 调节 重要的 DNA 损伤修复基因，以及 (vii) 抑制 CK1δ/ε 增强 IR 的杀伤作用， DNA 损伤化疗药物和 PARP 抑制剂。总的来说，这些发现支持 前提是 CK1δ 是 GBM 和其他难治性转移癌症的可利用靶点 到大脑。在目标 1 中，使用已经建立的关键路径分析、经过验证的研究操作 plan (ROP)，一种基于多参数优化的迭代药物化学方法 通过药物代谢和药代动力学研究增强策略，我们将开发和提供 优化的双重和亚型选择性脑渗透剂 CK1δ 和 CK1ε 抑制剂。功效和安全性 这些抑制剂将在我们的小鼠颅内人类异种移植模型中进行测试。在目标 2 中，我们将 (i) 识别由 CK1δ 活性修饰的完整侵袭相关蛋白，(ii) 阐明 CK1δ 如何 有助于 GBM 肿瘤细胞扩散； (iii) 确定CK1δ如何以及在哪个阶段控制方面 从外周到大脑的转移级联反应，以及 (iv) 阐明 CK1δ 在 调节神经胶质瘤干细胞样状态。在目标 3 中，我们将确定； (i) DN​​A损伤的MOA- 诱导 GBM 中基因组维持途径的 CK1δ 调节，以及 (ii) 定义安全裕度 与我们的主要 CK1δ/ε 抑制剂相关，是改善治疗的最有效组合 在GBM中。