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

 描述(申请人提供)：最近在佛罗里达州斯克里普斯研究所的鲁什实验室进行了高通量筛选和药物化学优化，发现了酪蛋白激酶1增量(CK1δ)和1 epsilon(CK1ε)的高效和选择性抑制剂。初步研究表明，这类嘌呤抑制物非常适合作为探针来确定CK1δ/CK1ε在许多人类癌症中的作用。尽管目前的铅化合物在动物模型中具有优异的效果，但这种先导剂的脑渗透率只有12%，不适合临床应用于脑癌的治疗。尽管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。迭代药物化学和DMPK参数将被用于开发安全、有效、口服生物利用和脑穿透的CK1δ/CK1ε抑制剂，用于治疗原发和转移性脑癌。 利用内部的SAR和DMPK数据，结合对大脑渗透特性的电子分析，将完成通过血脑屏障(BBB)靶向递送的新的嘌呤抑制剂的设计。首先，将致力于开发具有更好的物理化学性质以增强被动血脑屏障扩散的CK1δ/ε类似物。此外，设计和合成可用于BBB中小分子转运体主动转运的嘌呤类化合物，将通过可调节连接子在C2和C6位添加内源载体底物样基团来完成化学修饰。 由于只有几种化合物被FDA批准用于治疗脑癌，拟议中的工作的完成将提供一系列新的抑制剂，能够对数千名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.