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

基本信息

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
项目类别：
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

项目摘要

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.

高级神经胶质瘤，尤其是胶质母细胞瘤（GBM），预后异常差，并且取消向大脑转移，例如，肺和乳房与晚期有关疾病。值得注意的是，我们的Multi-Pi研究团队发现了酪蛋白激酶-1 Delta和Epsilon （CK1δ，CK1ε）是GBM的新治疗靶标。这个发现起源于一个小分子佛罗里达州斯克里普斯（Scripps Florida）的Roush Lab的屏幕，他确定了一类高潜力和选择性双重 CK1δ和CK1ε的抑制剂。然后，Duckett Lab的进一步研究表明；（i）11％的GBM 所有乳腺癌中有36％都放大了CSNK1D；（ii）GBM和某些乳腺癌包括向大脑转移的人表达CK1δ和Wnt/β-catenin转录水平的升高目标；（iii）表达CK1δ和CK1ε的脑转移性肺腺癌细胞，高度高对我们的抑制剂敏感；（iv）双CK1δ/ε抑制剂诱导GBM，乳房和肺的快速凋亡癌细胞在体内和体内肿瘤回归，但对正常的人上皮细胞没有毒性并且可以长期对小鼠进行施用，而无需观察到不利的副作用；（v）ck1Δ/ε 调节参与肿瘤细胞侵袭的关键因素的表达，（VI）CK1Δ/ε调节表达必需的DNA损伤修复基因，（vii）抑制CK1Δ/ε的抑制作用增强了IR的杀戮作用， DNA破坏化学治疗剂和PARP抑制剂。这些发现共同支持前提是CK1δ是GBM和其他难治性癌症的可利用目标到大脑。在AIM 1中，使用已经建立的关键路径分析，一项经过验证的研究操作计划（ROP），一种基于多参数优化的迭代医学化学方法药物代谢和药代动力学研究增强的策略，我们将开发和交付优化的双重和同工型选择性脑穿透性CK1δ和CK1ε抑制剂。功效和安全性这些抑制剂将在我们的颅内人体异种移植模型中进行测试。在AIM 2中，我们将（i）确定通过CK1δ活性修饰的入侵相关蛋白的完整铸件，（ii）阐明CK1δ如何有助于GBM肿瘤细胞扩散；（iii）确定ck1δ控制方面的方式和在哪个阶段从周围到大脑的转移级联反应，（iv）阐明了ck1δ在调节神经胶质瘤干细胞状状态。在AIM 3中，我们将确定；（i）DNA损伤的MOA- GBM中基因组维持途径的诱导CK1δ调节，（ii）定义安全边缘与我们的铅CK1Δ/ε抑制剂和最有效的组合相关在GBM中。