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:8631767
- 负责人:
- 金额:$ 48.43万
- 依托单位:
- 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:
- 关键词:AffinityAffinity ChromatographyAntineoplastic AgentsBiochemicalBiochemical GeneticsBiologicalBiological AssayBrainBreast Cancer CellCSNK1A1 geneCell LineCell physiologyCellsCephalicChemistryChronicCircadian RhythmsClinicColon CarcinomaCritical PathwaysCytoskeletonDNA DamageDerivation procedureDevelopmentDoseDrug KineticsFiberGeneticGlioblastomaGoalsGrantGrowthHousingHumanIn VitroKnock-in MouseKnockout MiceLeadLegal patentLinkLungMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMass Spectrum AnalysisMelanoma CellMetastatic MelanomaModelingMolecular ModelsMusNeurodegenerative DisordersNormal CellOrganic ChemistryPenetrationPharmaceutical ChemistryPharmaceutical PreparationsPhosphorylationPhosphotransferasesPhysiologicalPre-Clinical ModelProcessPropertyProtein IsoformsProtein-Serine-Threonine KinasesRegulationRenal carcinomaReportingResearchResistanceRoleSafetySerineSignal TransductionSleep DisordersSpecificityTestingTherapeuticTherapeutic StudiesThreonineTumor-DerivedUnited States National Institutes of HealthXenograft ModelXenograft procedureanaloganti-cancer therapeuticbasecancer cellcancer geneticscasein kinasecasein kinase Ichemotherapyconventional therapydrug developmentdrug metabolismefficacy testingimprovedin vivoinhibitor/antagonistmalignant breast neoplasmmelanomamolecular modelingmouse modelmutantneoplastic cellnovelnovel therapeuticsoverexpressionpre-clinicalpreclinical studypublic health relevancereceptorresponsesmall moleculetooltriple-negative invasive breast carcinomatumortumorigenic
项目摘要
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.
项目概要
我们研究团队的目标是优化和评估 δ 和抑制剂的化合物
酪蛋白激酶 1 (CK1¿/¿) 的 e 亚型。 CK1¿/¿ 是单体丝氨酸/苏氨酸蛋白激酶,
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
节奏。 CK1¿/¿ 的异常调节与多种癌症、神经退行性疾病和
睡眠障碍。重要的是,我们的研究团队结合了药物和合成方面的专业知识
有机化学和新疗法的推导(PI Dr. William Roush),与癌症相关
遗传学和临床前治疗研究(联合 PI 约翰·克利夫兰博士)以及药物开发和抗
癌症激酶疗法(联合 PI Dr. Derek Duckett)已经证明,我们新的内部和高度
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作用
(黑色素瘤、乳腺癌和胶质母细胞瘤 [GBM])细胞效力。此外,离体遗传学研究
黑色素瘤和三阴性乳腺癌细胞表明我们的化合物的抗肿瘤活性是
与 CK1¿/¿ 活性的抑制一致,并且试点原位异种移植研究表明,我们的
CK1¿/¿ 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
中空纤维测定表明,我们的 CK1¿/¿ 抑制剂对其他人类具有显着的效力
癌症包括结肠癌、肺癌和肾癌。重要的是,我们的先导化合物通常没有毒性,
因为这些 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 21 天 BID 慢性给药中具有良好的耐受性。因此,我们假设
CK1¿/¿ 亚型是癌症治疗开发中极具吸引力的靶点。瞄准
1 我们的主要 CK1¿/¿ 抑制剂的类似药物特性(包括脑渗透)将使用以下方法进行优化
重复药物化学、DMPK 和功效筛选。我们将采用严格的研究运营计划
优先考虑 CK1¿/¿ 抑制剂,这将流入目标 2 和 3 中概述的研究。在目标 2 中,使用电池
通过遗传方法,我们将严格测试我们的先导化合物的抗癌活性和
优化的类似物完全是由于 CK1¿ 和/或 CK1¿ 的抑制,或是否有其他生物学相关
目标有助于发挥其效力。使用小鼠模型,我们还测试了 CK1¿ 和/或 CK1¿
突变 BRaf 驱动的黑色素瘤的发展。最后,在目标 3 中,将对顶级化合物进行测试
使用小鼠和人类黑色素瘤、人类三阴性乳腺癌的异种移植物的抗肿瘤功效,
以及原发性人类 GBM 的治疗,既可以作为单一药物,也可以与常规疗法联合使用。我们
提交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
CK1¿/¿ 将可作为针对多种耐药性恶性肿瘤的广谱疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
WILLIAM R ROUSH其他文献
WILLIAM R ROUSH的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('WILLIAM R ROUSH', 18)}}的其他基金
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 - 财政年份:2014
- 资助金额:
$ 48.43万 - 项目类别:
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:
9049453 - 财政年份:2014
- 资助金额:
$ 48.43万 - 项目类别:
SYNTHESIS OF INHIBITORS OF PARASITIC CYSTEINE PROTEASES
寄生半胱氨酸蛋白酶抑制剂的合成
- 批准号:
6338609 - 财政年份:2000
- 资助金额:
$ 48.43万 - 项目类别:
SYNTHESIS OF INHIBITORS OF PARASITIC CYSTEINE PROTEASES
寄生半胱氨酸蛋白酶抑制剂的合成
- 批准号:
6099783 - 财政年份:1999
- 资助金额:
$ 48.43万 - 项目类别:
相似海外基金
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10506915 - 财政年份:2021
- 资助金额:
$ 48.43万 - 项目类别:
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10325006 - 财政年份:2021
- 资助金额:
$ 48.43万 - 项目类别:
SBIR Phase I: A New Class of Immobilized Metal Affinity Chromatography Resins
SBIR 第一阶段:一类新型固定金属亲和色谱树脂
- 批准号:
1746198 - 财政年份:2018
- 资助金额:
$ 48.43万 - 项目类别:
Standard Grant
Marine speciation of nickel using immobilized nickel affinity chromatography
使用固定镍亲和色谱法测定镍的海洋形态
- 批准号:
512537-2017 - 财政年份:2017
- 资助金额:
$ 48.43万 - 项目类别:
University Undergraduate Student Research Awards
I-Corps: Commercialization of Immobilized Metal Affinity Chromatography Resins Based on Nanomaterials
I-Corps:基于纳米材料的固定化金属亲和层析树脂的商业化
- 批准号:
1404605 - 财政年份:2014
- 资助金额:
$ 48.43万 - 项目类别:
Standard Grant
Antibody Purification via Affinity Chromatography that Utilizes the Unconventional Nucleotide Binding Site
利用非常规核苷酸结合位点通过亲和色谱法纯化抗体
- 批准号:
1263713 - 财政年份:2013
- 资助金额:
$ 48.43万 - 项目类别:
Continuing Grant
Development of multivalent DNA network based affinity chromatography diagnostics for isolating circulating tumour cells
开发基于多价 DNA 网络的亲和色谱诊断法,用于分离循环肿瘤细胞
- 批准号:
425749-2012 - 财政年份:2012
- 资助金额:
$ 48.43万 - 项目类别:
Postgraduate Scholarships - Master's
Next-Generation Affinity Chromatography with PEGylated Ligands
使用聚乙二醇化配体的新一代亲和色谱法
- 批准号:
1159886 - 财政年份:2012
- 资助金额:
$ 48.43万 - 项目类别:
Standard Grant
Immobilized zirconium ion affinity chromatography for specific enrichment of phosphoproteins
用于磷蛋白特异性富集的固定化锆离子亲和层析
- 批准号:
19560760 - 财政年份:2007
- 资助金额:
$ 48.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accelerating drug discovery using frontal affinity chromatography/mass spectrometry
使用正面亲和色谱/质谱加速药物发现
- 批准号:
234753-2000 - 财政年份:2003
- 资助金额:
$ 48.43万 - 项目类别:
Collaborative Research and Development Grants