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)

• 批准号: 8631767
• 负责人: WILLIAM R ROUSH
• 金额: $ 48.43万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 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/8631767
• 关键词: Affinity; Affinity Chromatography; Antineoplastic Agents; Biochemical; Biochemical Genetics; Biological; Biological Assay; Brain; Breast Cancer Cell; CSNK1A1 gene; Cell Line; Cell physiology; Cells; Cephalic; Chemistry; Chronic; Circadian Rhythms; Clinic; Colon Carcinoma; Critical Pathways; Cytoskeleton; DNA Damage; Derivation procedure; Development; Dose; Drug Kinetics; Fiber; Genetic; Glioblastoma; Goals; Grant; Growth; 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; Threonine; 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; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; melanoma; molecular modeling; mouse model; mutant; neoplastic cell; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; public health relevance; receptor; response; small molecule; tool; triple-negative invasive breast carcinoma; tumor; tumorigenic

Project Summary 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 (CK1¿/¿). CK1¿/¿ are monomeric serine/threonine protein kinases that regulate diverse cellular processes including Wnt signaling, the DNA damage response and circadian rhythms. Aberrant regulation of CK1¿/¿ 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 CK1¿/¿ 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 CK1¿/¿ activity and pilot orthotopic xenograft studies have shown that our CK1¿/¿ inhibitors have potent anti-melanoma and anti-GBM activity in vivo. In addition, NCI-60 screens and hollow fiber assays have shown that our CK1¿/¿ 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 CK1¿/¿ 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 CK1¿/¿ isoforms are highly attractive targets for the development of cancer therapeutics. In Aim 1 the drug-like properties-including brain penetration-of our lead CK1¿/¿ inhibitors will be optimized using reiterative medicinal chemistry, DMPK, and efficacy screens. We will use a rigorous research operating plan to prioritize CK1¿/¿ inhibitors which will flow into studies outlined in Aims 2 and 3. In Aim 2, 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 CK1¿ and/or CK1¿, or whether other biologically relevant targets contribute to their potency. Using mouse models we also test the roles of CK1¿ and/or CK1¿ 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 CK1¿/¿ that will be useful as broad-spectrum therapeutics against a host of resistant malignancies.

项目摘要 我们研究团队的目标是优化和评估是三角洲抑制剂的化合物 酪蛋白激酶1（CK1¿/¿）的埃普斯龙同工型。 CK1€ /是单体丝氨酸 /苏氨酸蛋白激酶， 调节包括Wnt信号，DNA损伤响应和昼夜节律在内的各种细胞过程 节奏。在各种癌症以及神经退行性和 睡眠障碍。重要的是，我们的研究团队结合了医学和合成方面的专业知识 有机化学和新疗法的推导（PI William Roush博士）与癌症患者 遗传学和临床前治疗研究（Co-Pi John Cleveland博士）和药物开发和抗 癌症激酶疗法（Co-Pi Derek Duckett博士）证明了我们的新内部和高度 选择性和ATP竞争性CK1？ /»抑制剂具有非常低的纳摩尔生化和抗癌药 （黑色素瘤，乳腺癌和胶质母细胞瘤[GBM]）细胞效率。此外，在体内遗传研究 黑色素瘤和三阴性乳腺癌细胞表明我们化合物的抗肿瘤活性是 与抑制CK1¿ /¿活动和试验原位型谱研究一致的已经表明，我们 CK1®抑制剂在体内具有潜在的抗黑色素瘤和抗GBM活性。此外，NCI-60屏幕和 空心纤维测定表明，我们的CK1»抑制剂对其他人具有显着的效力 包括结肠，肺癌和肾癌在内的癌症。重要的是，我们的铅化合物通常不是有毒的 由于这些ck1… /»抑制剂不会损害某些肿瘤类型或正常细胞的生长或存活 在临床前研究中，它们在慢性21天的出价剂量中得到很好的耐受性。那我们假设 CK1？ /€是癌症疗法发展的高度吸引力的靶标。目标 1使用铅CK1抑制剂（包括脑渗透）的药物样特性，使用抑制剂进行优化 Reiterator医学化学，DMPK和有效屏幕。我们将使用严格的研究工作计划 用电池在AIM 2中优先考虑CK1？ /€ 在遗传方法中，我们将严格测试铅化合物的抗癌活性和 优化的类似物仅是由于抑制了CK1¿和/或CK1，或者是否其他与生物学相关的 目标有助于他们的效力。使用鼠标模型，我们还测试了CK1¿和/或CK1缺的作用 突变体BRAF驱动的黑色素瘤的发展。最后，在AIM 3中，将对顶级化合物进行测试 使用小鼠和人类黑色素瘤的Xenographographics，人类三重阴性乳腺癌，抗肿瘤效率， 和原发性GBM的单一药物以及常规疗法的结合。我们 提出我们的研究团队将产生针对目标的新，潜在和安全的反癌代理 CK1®将作为针对许多耐药性恶性肿瘤的广谱疗法有用。