Targeting Casein Kinase 1d/e (CK1d/1e) in Cancer Therapeutics

癌症治疗中的靶向酪蛋白激酶 1d/e (CK1d/1e)

基本信息

批准号：
9049453
负责人：
WILLIAM R ROUSH
金额：
$ 49.2万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049453
关键词：
Affinity Affinity Chromatography Antineoplastic Agents Biochemical Biochemical Genetics Biological Biological Assay Brain Breast Cancer Cell Cell Line Cell physiology Cells Chemistry Chronic Circadian Rhythms Clinic Colon Carcinoma Critical Pathways Cytoskeleton DNA Damage Derivation procedure Development Dose Drug Kinetics Fiber Genetic study Glioblastoma Goals Grant Growth Health Housing Human In Vitro Knock-in Mouse Knockout Mice Lead Legal patent Link Lung Maintenance Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Melanoma Cell Metastatic Melanoma Modeling Molecular Models Mus Neurodegenerative Disorders Normal Cell Organic Chemistry Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiological Pre-Clinical Model Process Property Protein Isoforms Protein-Serine-Threonine Kinases Regulation Renal carcinoma Reporting Research Resistance Role Safety Serine Signal Transduction Sleep Disorders Specificity Testing Therapeutic Therapeutic Studies Tumor-Derived United States National Institutes of Health Xenograft Model Xenograft procedure analog anti-cancer therapeutic base cancer cell cancer genetics casein kinase casein kinase I chemotherapy conventional therapy drug development drug metabolism efficacy testing genetic approach improved in vivo inhibitor/antagonist knock-down malignant breast neoplasm melanoma molecular modeling mouse model mutant nanomolar neoplastic cell novel novel therapeutics overexpression pre-clinical preclinical study receptor response small molecule small molecule inhibitor tool triple-negative invasive breast carcinoma tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The goal of our research team is to optimize and evaluate compounds that are inhibitors of the delta and epsilon isoforms of casein kinase 1 (CK1δ/ϵ). CK1δ/ϵ are monomeric serine/threonine protein kinases that regulate diverse cellular processes including Wnt signaling, the DNA damage response and circadian rhythms. Aberrant regulation of CK1δ/ϵ is implicated in various cancers, and in neurodegenerative and sleep disorders. Importantly, our research team, which combines expertise in medicinal and synthetic organic chemistry and the derivation of novel therapeutics (PI Dr. William Roush), with those in cancer genetics and preclinical therapeutic studies (co-PI Dr. John Cleveland) and drug development and anti- cancer kinase therapeutics (co-PI Dr. Derek Duckett) has demonstrated that our new in-house and highly selective and ATP competitive CK1δ/ϵ inhibitors have very low nanomolar biochemical and anti-cancer (melanoma, breast cancer and glioblastoma [GBM]) cell potency. Furthermore, ex vivo genetic studies in melanoma and triple-negative breast cancer cells indicate that the anti-tumor activity of our compounds is consistent with inhibition of CK1δ/ϵ activity and pilot orthotopic xenograft studies have shown that our CK1δ/ϵ inhibitors have potent anti-melanoma and anti-GBM activity in vivo. In addition, NCI-60 screens and hollow fiber assays have shown that our CK1δ/ϵ inhibitors have remarkable potency against other human cancers that include colon, lung and renal cancer. Importantly, our lead compounds are not generally toxic, as these CK1δ/ϵ inhibitors do not compromise the growth or survival of some tumor types or of normal cells and they are well tolerated in chronic 21 day BID dosing in pre-clinical studies. Thus, we hypothesize that the CK1δ/ϵ isoforms are highly attractive targets for the development of cancer therapeutics. In Aim 1 the drug-like properties - including brain penetration - of our lead CK1δ/ϵ inhibitors will be optimized using reiterative medicinal chemistry, DMPK, and efficacy screens. We will use a rigorous research operating plan to prioritize CK1δ/ϵ inhibitors which will flow into studies outlined in Aims 2 and 3. In Aim , using a battery of genetic approaches, we will rigorously test whether the anti-cancer activity of our lead compounds and optimized analogs is solely due to inhibition of CK1δ and/or CK1ϵ, or whether other biologically relevant targets contribute to their potency. Using mouse models we also test the roles of CK1δ and/or CK1ϵ in the development of mutant BRaf-driven melanoma. Finally, in Aim 3, top compounds will be tested for their anti-tumor efficacy using xenografts of mouse and human melanoma, human triple negative breast cancer, and of primary human GBM both as single agents and in combination with conventional therapies. We submit that our research team will generate a cast of new, potent and safe anti-cancer agents targeting CK1δ/ϵ that will be useful as broad-spectrum therapeutics against a host of resistant malignancies.

描述（由适用提供）：我们的研究团队的目标是优化和评估酪蛋白激酶1（CK1Δ/ϵ）的抑制剂和Epsilon同工型的化合物。 CK1Δ/ϵ是单体丝氨酸/苏氨酸蛋白激酶，可调节包括Wnt信号传导，DNA损伤反应和昼夜节律的各种细胞过程。 CK1δ/ϵ的异常调节与各种癌症以及神经退行性和睡眠障碍有关。重要的是，我们的研究团队结合了医学和合成有机化学方面的专业知识以及新型疗法的推导（PI William Roush博士），以及癌症遗传学和临床前疗法研究（Co-Pi John Cleveland博士）和药物开发以及我们的反癌激酶治疗（CO-PI Derek Derek Dective and House and atp ausess）的癌症遗传学和临床前治疗研究的研究团队（Co-Pi）和抗癌竞争。抑制剂具有非常低的纳摩尔生化和抗癌（黑色素瘤，乳腺癌和胶质母细胞瘤[GBM]）细胞效应。此外，在黑色素瘤和三阴性乳腺癌细胞中的体内遗传研究表明，我们化合物的抗肿瘤活性与CK1Δ/ϵ活性的抑制和试验性正交异种移植研究一致，我们的CK1Δ/ϵ抑制剂具有潜在的抗甲状腺瘤和抗抗活性。此外，NCI-60筛选和空心纤维测定表明，我们的CK1δ/抑制剂对包括结肠，肺癌和肾癌在内的其他人类癌症具有显着的效力。重要的是，我们的铅化合物通常不是有毒的，因为这些CK1Δ/ϵ抑制剂不会损害某些肿瘤类型或正常细胞的生长或存活，并且在临床前研究中，它们在慢性21天中的耐受性良好。这是我们假设CK1Δ/ϵ同工型是癌症治疗发展的高度吸引力的靶标。在AIM 1中，我们将使用重新的医学化学，DMPK和有效筛选来优化我们铅CK1Δ/ϵ抑制剂的类似药物样特性 - 包括脑穿透。我们将使用严格的研究工作计划来确定CK1δ/ϵ抑制剂的优先级，该抑制剂将流入目标2和3中概述的研究。在AIM中，使用小鼠模型，我们还测试了CK1δ和/或CK1ϵ在突变BRAF驱动的黑色素瘤发展中的作用。最后，在AIM 3中，将使用小鼠和人类黑色素瘤的异种移植物，人类三乳腺癌和原代人GBM作为单一药物以及与常规疗法结合的原代人GBM的异种移植物来测试其抗肿瘤效率。我们认为，我们的研究团队将产生针对CK1Δ/ϵ的新的，潜在和安全的抗癌代理，这将是针对许多抵抗力的Malignancys的广谱疗法。