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

开发用于治疗脑癌的酪蛋白激酶 1d 和 1e 抑制剂

• 批准号: 9045946
• 负责人: Andrii Monastyrskyi
• 金额: $ 5.43万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045946
• 关键词: Accounting; Active Biological Transport; Adult; Affect; Animal Model; Apoptosis; Bioavailable; Biochemical; Biochemistry; Biological; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast; Cancer Biology; Cancer Etiology; Cancer Model; Cell Line; Cells; Central Nervous System Neoplasms; Cessation of life; Chemicals; Collaborations; Computer Simulation; Cranial Irradiation; Data; Development; Diagnosis; Dialysis procedure; Diffusion; Disease; Distant; Drug Kinetics; ERBB2 gene; Effectiveness; Equilibrium; Excision; FDA approved; Florida; Glioblastoma; Goals; Housing; Human; In Vitro; Kinetics; Laboratories; Lead; Life Expectancy; Lung; MDA MB 231; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Metastatic malignant neoplasm to brain; Modification; Mus; Nature; Neoplasm Metastasis; Oral; Outcome; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Property; Purine Antagonist; Purines; Recurrent tumor; Refractory; Research Institute; Resistance; Role; Series; Signal Pathway; Structure; Surgically-Created Resection Cavity; Therapeutic; Work; Xenograft Model; analog; base; beta catenin; brain surgery; brain tissue; carrier mediated transport; casein kinase; casein kinase I; clinical application; design; drug metabolism; effective therapy; high throughput screening; improved; in vivo; inhibitor/antagonist; insight; irradiation; malignant breast neoplasm; neoplastic cell; novel; outcome forecast; palliative; pre-clinical; public health relevance; scaffold; small molecule; targeted delivery; tool; treatment strategy; tumor; uptake

 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.

 描述（由申请人提供）：斯克里普斯研究所 Roush 实验室经过高通量筛选和药物化学优化，最近鉴定出酪蛋白激酶 1 delta (CK1δ) 和 1 epsilon (CK1ε) 的高效选择性抑制剂佛罗里达州。初步研究表明，此类嘌呤抑制剂非常适合作为探针来定义 CK1δ/CK1ε 在人类宿主中的作用。尽管目前的先导化合物在动物模型中具有非凡的功效，但先导药物的脑渗透率仅为 12%，不适合临床应用治疗脑肿瘤。最有效的治疗选择仍然是全脑放疗和手术，而药物本质上主要是姑息性或支持性的。迭代药物化学和 DMPK 参数将用于开发安全、有效、口服生物可利用和脑渗透性的 CK1δ/CK1ε。用于治疗原发性和转移性脑癌的抑制剂。 利用内部 SAR 和 DMPK 数据以及脑渗透特性的计算机分析，将完成针对血脑屏障 (BBB) 递送的新型嘌呤抑制剂的设计。首先，将完成 CK1δ/ε 的开发。此外，将通过 C2 和 C6 位点的化学修饰来设计和合成用于 BBB 中小分子转运蛋白主动转运的嘌呤衍生物。通过可调节的连接体添加内源性载体底物样部分。 目前只有少数化合物被 FDA 批准用于治疗脑癌，完成拟议的工作将提供一系列新型抑制剂，能够对数千名受这种可怕疾病影响的人产生重大影响。