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: 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
• 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

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价作为酪蛋白激酶1（CK 1 δ/CK 2）δ和β亚型抑制剂的化合物。CK 1 δ/CK 2是单体丝氨酸/苏氨酸蛋白激酶，其调节多种细胞过程，包括Wnt信号传导、DNA损伤反应和昼夜节律。CK 1 δ/CK 2的异常调节与各种癌症、神经退行性疾病和睡眠障碍有关。重要的是，我们的研究团队，结合了医学和合成有机化学的专业知识和新疗法的衍生，（PI Dr. William Bauh），与癌症遗传学和临床前治疗研究的研究人员（共同PI博士约翰克利夫兰）和药物开发和抗癌激酶治疗（共同PI Dr. Derek Duckett）已经证明，我们新的内部高选择性和ATP竞争性CK 1 δ/CK 2抑制剂具有非常低的纳摩尔生化和抗癌活性，（黑色素瘤、乳腺癌和胶质母细胞瘤[GBM]）细胞效力。此外，在黑色素瘤和三阴性乳腺癌细胞中的离体遗传研究表明，我们的化合物的抗肿瘤活性与CK 1 δ/CK 2活性的抑制一致，并且初步原位异种移植研究表明，我们的CK 1 δ/CK 2抑制剂在体内具有有效的抗黑色素瘤和抗GBM活性。此外，NCI-60筛选和中空纤维试验表明，我们的CK 1 δ/β抑制剂对其他人类癌症（包括结肠癌、肺癌和肾癌）具有显著的效力。重要的是，我们的先导化合物通常没有毒性，因为这些CK 1 δ/CK 2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，它们在长期21天BID给药中耐受良好。因此，我们假设CK 1 δ/CK 2亚型是开发癌症治疗剂的高度有吸引力的靶点。在目标1中，我们的主要CK 1 δ/β抑制剂的药物样特性-包括脑渗透-将使用渐进式药物化学，DMPK和疗效筛选进行优化。我们将使用严格的研究操作计划，优先考虑CK 1 δ/CK 2抑制剂，这些抑制剂将流入目标2和3中概述的研究。在Aim中，使用一系列遗传方法，我们将严格测试我们的先导化合物和优化的类似物的抗癌活性是否仅仅是由于CK 1 δ和/或CK 1 β的抑制，或者其他生物学相关靶点是否有助于其效力。使用小鼠模型，我们还测试了CK 1 δ和/或CK 1 β在突变型BRaf驱动的黑色素瘤发展中的作用。最后，在目标3中，将使用小鼠和人黑素瘤、人三阴性乳腺癌和原发性人GBM的异种移植物作为单一药剂和与常规疗法组合来测试顶级化合物的抗肿瘤功效。我们提出，我们的研究团队将产生一系列新的，有效的和安全的抗癌药物，靶向CK 1 δ/CK 2，这将是有用的广谱治疗对许多耐药恶性肿瘤。