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， 转移到大脑，例如从肺和乳房转移到大脑， 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 δ和β (CK1δ、CK 1 ε）是治疗GBM的新靶点。这一发现源于一种小分子 筛选由斯克里普斯佛罗里达，谁确定了一类高度有效的和选择性的双重 CK 1 δ和CK 1 ε的抑制剂。Duckett实验室的进一步研究表明：（i）11%的GBM 36%的乳腺癌具有扩增的CSNK 1D;（ii）GBM和某些乳腺癌，包括 那些转移到脑的细胞表达CK 1 δ和Wnt/β-catenin转录水平升高， （iii）表达CK 1 δ和CK 1 ε且高度表达CK 1 δ和CK 1 ε的脑转移性肺腺癌细胞; 对我们的抑制剂敏感;（iv）双重CK 1 δ/ε抑制剂诱导GBM、乳腺和肺的快速凋亡 体外癌细胞和体内肿瘤消退，但对正常人上皮细胞无毒 并且可以长期每天给予小鼠而没有可观察到的不良副作用;（v）CK 1 δ/ε 调节参与肿瘤细胞侵袭的关键因子的表达，（vi）CK 1 δ/ε调节 必需的DNA损伤修复基因，和（vii）抑制CK 1 δ/ε增强IR的杀伤作用， DNA损伤化疗剂和PARP抑制剂。这些发现共同支持了 前提是CK 1 δ是GBM和其他转移性难治性癌症的可利用靶点， 到大脑。在目标1中，使用已经建立的关键路径分析， ROP计划，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的策略，我们将开发和提供 优化的双重和同种型选择性脑渗透剂CK 1 δ和CK 1 ε抑制剂。疗效和安全性 这些抑制剂将在我们的小鼠颅内人异种移植模型中进行测试。在目标2中，我们将（i） 鉴定由CK 1 δ活性修饰的侵袭相关蛋白的全部类型，（ii）阐明CK 1 δ 有助于GBM肿瘤细胞扩散;（iii）确定如何以及在哪个阶段CK 1 δ控制方面 的转移级联从周边到大脑，（iv）阐明CK 1 δ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CK 1 δ-调节GBM中的基因组维持途径，以及（ii）定义安全范围 与我们的主要CK 1 δ/ε抑制剂相关，是改善治疗的最有效组合 在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.