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

高级别胶质瘤，特别是胶质母细胞瘤(GBM)，预后极差，并伴有癌症。 转移到大脑，例如从肺和乳房转移与晚期 疾病。值得注意的是，我们的多PI研究团队发现酪蛋白激酶-1增量和epsilon CK1δ、CK1ε是治疗基底膜的新靶点。这一发现源于一种小分子 佛罗里达州斯克里普斯的Roush实验室进行了筛选，他们发现了一类高度有效和选择性的双重基因 CK1δ和CK1ε的抑制剂。Duckett实验室的进一步研究表明；(I)11%的GBM 所有乳腺癌中有36%扩增了CSNK1D；(Ii)GBM和某些乳腺癌，包括 转移到大脑的肿瘤表达高水平的CK1δ和Wnt/β-Catenin转录 靶细胞；(Iii)脑转移肺腺癌细胞，表达CK1δ和CK1ε， 对我们的抑制剂敏感；(Iv)双CK1δ/ε抑制剂诱导基底膜、乳腺和肺快速凋亡 癌细胞在体外，肿瘤在体内消退，但对正常人上皮细胞无毒 可以长期每天给小鼠服用，没有可观察到的副作用；(V)CK1δ/ε 调节肿瘤细胞侵袭的关键因子的表达，(Vi)CK1δ/ε调节肿瘤细胞侵袭的关键因子的表达 (Vii)抑制CK1δ/ε可增强IR的杀伤作用， 破坏DNA的化疗药物和PARP抑制剂。总体而言，这些发现支持 假设CK1δ是基底膜和其他转移的难治性癌症的可利用靶点 对大脑的影响。在目标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 基于多参数优化的迭代药物化学方法--计划(ROP) 通过药物代谢和药代动力学研究加强战略，我们将开发和交付 优化的双重和异构体选择性脑穿透性细胞角蛋白1δ和细胞角蛋白1ε抑制剂。安慰剂的有效性和安全性 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) 鉴定由CK1δ活性修饰的侵袭相关蛋白(S)的全部铸型，(II)阐明CK1δ是如何 有助于基底膜肿瘤细胞扩散；(Iii)确定如何以及在哪个阶段CK1δ控制方面 以及(Iv)阐明CK1δ在肿瘤转移中的作用。 调节神经胶质瘤干细胞样状态。在目标3中，我们将确定：(I)DNA损伤的MOA- 诱导的CK1δ-调节基底膜的基因组维持途径，以及(Ii)确定安全裕度 与我们的领先细胞角蛋白1δ/ε抑制剂相关，以及改善治疗的最有效组合 单位为GBM。

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.