Development of Casein Kinase 1d and 1e Inhibitors for Treatment of Brain Cancer

 描述（由申请人提供）：最近，在斯克里普斯研究所的Roush实验室中，通过高通量筛选和药物化学优化，发现了酪蛋白激酶1 δ（CK 1 δ）和1 ε（CK 1 ε）的高效选择性抑制剂。佛罗里达。初步研究表明，这类嘌呤抑制剂非常适合作为探针，以确定CK 1 δ/CK 1 ε在人类癌症宿主中的作用。尽管目前的先导化合物在动物模型中具有优异的效果，但先导剂的脑渗透率仅为12%，这不适合用于治疗脑癌的临床应用。虽然最近在治疗脑肿瘤方面取得了相当大的进展，但最有效的治疗选择仍然是全脑放疗和手术，而药物治疗大多是姑息性或支持性的。将使用迭代药物化学和DMPK参数开发安全、有效、口服生物可利用和脑渗透性CK 1 δ/CK 1 ε抑制剂，用于治疗原发性和转移性脑癌。 使用内部SAR和DMPK数据以及脑渗透性质的计算机分析，将完成用于通过血脑屏障（BBB）靶向递送的新嘌呤抑制剂的设计。首先，将致力于开发具有改善的物理化学性质的CK 1 δ/ε类似物以增强被动BBB扩散。此外，用于通过BBB中存在的小分子转运蛋白主动转运的嘌呤衍生物的设计和合成将通过经由可调节接头添加内源性载体底物样部分在C2和C6位置进行化学修饰来完成。 由于FDA批准用于治疗脑癌的化合物为数不多，完成这项工作将提供一系列新的抑制剂，能够对成千上万受这种可怕疾病影响的人产生重大影响。

 DESCRIPTION (provided by applicant): Highly potent and selective inhibitors of casein kinase 1 delta (CK1δ) and 1 epsilon (CK1ε) were recently identified as a result of high-throughput screening and medicinal chemistry optimization in the Roush laboratory at The Scripps Research Institute Florida. Preliminary studies indicate that this class of purine inhibitors is ideally suited to serve as probes to define the roles of CK1δ/CK1ε in a host of human cancers. Despite exceptional effectiveness of the current lead compound in animal models, the brain penetration of the lead agent is only 12% which is not suitable for clinical applications for treatment of brain cancer. Although considerable progress has been recently made in the treatment brain tumors, the most effective treatment options remain whole-brain radiation and surgery while medication is mostly palliative or supportive in nature. Iterative medicinal chemistry and DMPK parameters will be used to develop safe, potent, orally bioavailable and brain penetrant CK1δ/CK1ε inhibitors for treating primary and metastatic brain cancer. Using in-house SAR and DMPK data accompanied with in silico analysis of brain penetration properties, the design of new purine inhibitors for targeted delivery through the blood-brain barrier (BBB) will be accomplished. Firstly, the development of CK1δ/ε analogs with improved physicochemical properties to enhance passive BBB diffusion will be pursed. Furthermore, the design and synthesis of purine derivatives for active transport by small molecule transporters presented in BBB will be accomplished by chemical modification at C2 and C6 positions by addition of endogenous carrier substrate-like moieties via adjustable linkers. With only a handful compounds approved by the FDA for treatment of brain cancer, completion of the proposed work will provide with a novel series of inhibitors capable of producing a significant impact on the thousands affected by this horrific disease.