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：
8840911
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/8840911
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 malignant breast neoplasm melanoma molecular modeling mouse model mutant neoplastic cell novel novel therapeutics overexpression pre-clinical preclinical study receptor response small molecule 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（由申请人提供）：我们研究团队的目标是优化和评估酪蛋白激酶 1 (CK1δ/ϵ) δ 和 ε 亚型抑制剂的化合物，CK1δ/ϵ 是调节单体丝氨酸/苏氨酸蛋白激酶。 CK1δ/ε 的异常调节与多种细胞过程有关，包括 Wnt 信号传导、DNA 损伤反应和昼夜节律。重要的是，我们的研究团队将药物和合成有机化学以及新型疗法的推导方面的专业知识（PI Dr. William Roush）与癌症遗传学和临床前治疗研究（共同- PI 博士 John Cleveland）和药物开发和抗癌激酶疗法（联合 PI 博士 Derek Duckett）已经证明，我们新的内部、高选择性和 ATP 竞争性 CK1δ/ϵ 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]）细胞效力此外，黑色素瘤和三阴性乳腺癌细胞的离体遗传学研究表明，我们的化合物的抗肿瘤活性与抑制作用一致。 CK1δ/ε 活性和试点原位异种移植研究表明，我们的 CK1δ/ε 抑制剂在体内具有有效的抗黑色素瘤和抗 GBM 活性。 NCI-60 筛选和中空纤维测定表明，我们的 CK1δ/ϵ 抑制剂对其他人类癌症（包括结肠癌、肺癌和肾癌）具有显着的功效，重要的是，我们的先导化合物通常没有毒性，因为这些 CK1δ/ϵ 抑制剂没有毒性。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，它们在长期 21 天 BID 给药中具有良好的耐受性。因此，我们追求 CK1δ/ε。同工型是癌症治疗开发中极具吸引力的靶标，在目标 1 中，我们将使用重复药物化学、DMPK 和功效筛选来优化我们的主要 CK1δ/ε 抑制剂的药物特性（包括脑渗透）。严格的研究操作计划，优先考虑 CK1δ/ϵ 抑制剂，这将流入目标 2 和 3 中概述的研究。在目标中，我们将使用一系列遗传方法，严格测试是否我们的先导化合物和优化类似物的抗癌活性仅归因于 CK1δ 和/或 CK1ϵ 的抑制，或者其他生物学相关靶点是否有助于其效力，我们还使用小鼠模型测试了 CK1δ 和/或 CK1ϵ 在癌症中的作用。最后，在目标 3 中，将使用小鼠和人类黑色素瘤、人类三阴性乳腺的异种移植物来测试顶级化合物的抗肿瘤功效。我们认为，我们的研究团队将开发出一系列针对 CK1δ/ε 的新型、有效且安全的抗癌药物，这些药物将作为广谱药物发挥作用。针对许多耐药恶性肿瘤的治疗方法。