SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy
SUMO1 抑制化合物作为胶质母细胞瘤治疗的新型抗癌药物
基本信息
- 批准号:10054183
- 负责人:
- 金额:$ 38.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-15 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntineoplastic AgentsAutomobile DrivingBiochemical ReactionBiological AssayBlood - brain barrier anatomyBrainCDC2 geneCDK4 geneCell Culture TechniquesCell CycleCell modelCell physiologyCellsClinicClinical TreatmentCopy Number PolymorphismDataDeletion MutationDrug CompoundingDrug KineticsDrug ScreeningEnzyme InhibitionEnzymesEvaluationGenomicsGlioblastomaGoalsGrowthHumanImmunohistochemistryIn VitroLegal patentLibrariesLinkLysineMalignant NeoplasmsMalignant neoplasm of brainMediatingModelingModificationMolecular Mechanisms of ActionMutationNamesPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacotherapyPhosphorylationPhosphotransferasesPolyubiquitinPost-Translational Protein ProcessingProtein FamilyProtein KinaseProteinsRecurrenceReportingResistanceRetinoblastoma ProteinSafetySiteSmall Interfering RNATechnologyTestingTherapeutic EffectTimeTissuesToxicity TestsTreatment EfficacyUbiquitinUbiquitin-Conjugating EnzymesUbiquitinationWorkXenograft ModelXenograft procedurebasecancer stem cellcancer therapycell growthclinical developmentcyclin-dependent kinase 6effective therapyenzyme substrategenetic regulatory proteinin vivoinhibitor/antagonistknock-downnext generation sequencingnovelnovel anticancer drugpreclinical developmentprotein degradationscreeningself-renewalsmall moleculetumor progressiontumorigenicubiquitin-protein ligase
项目摘要
Our ultimate goal is to develop novel and effective treatments of glioblastoma, the most common and lethal
human brain cancer. To achieve this goal, we propose to develop the SUMO1 inhibition compound (SMIC1) as
a new anticancer drug for glioblastoma therapy. SUMO1 (small ubiquitin-like modifier-1) is a small regulatory
protein that is linked to substrate proteins through enzymatic reactions. SUMO1 conjugation of its substrate
proteins controls the cellular function of substrate proteins. In our recent work, we have revealed that SUMO1
conjugation pathway is overactive in glioblastoma and drives the cancer progression. To target this pathway,
we have developed glioblastoma cell-based SUMO1 assays for drug screening and identified the SMIC1 from
the NCI drugable compound library. In the efforts of preclinical development of SMIC1 as an anticancer drug,
we have followed the FDA guidance for nonclinical evaluation of new anticancer agents and tested the toxicity
and pharmacokinetics (PK) of SMIC1 and demonstrated that SMIC1 has an acceptable safety margin and
drugable PK features in animals. In systemic administration, SMIC1 can be quickly delivered to brains through
the blood brain barrier (BBB) and effectively inhibits glioblastoma xenograft growth.
In search of target proteins, we have shown that cyclin-dependent kinase-6 (CDK6) is a substrate of both
SUMO1 and ubiquitin (UB). SUMO1-CDK6 conjugation blocks CDK6 ubiquitination and the UB-mediated
degradation and thus stabilizes CDK6 kinase for driving cell growth through phosphorylation of retinoblastoma
protein-1 (RB1); thus, SMIC1 treatment blocks SUMO1-CDK6 conjugation and eliminates CDK6-RB1 pathway.
On the other hand, CDK4/6 inhibitors have been developed targeting CDK4/6-RB1 pathway and they are now
in clinic for cancer therapies. RB1 deletion and mutation occurs in about 11% glioblastomas and results in the
cancer resistance to CDK4/6 inhibitors. In contrast, we have shown that SMIC1 can overcome the resistance
through inhibition of various SUMO1 substrate proteins. The objective of this proposal is to develop SMIC1 as
a new anticancer drug for treatment of glioblastomas. To achieve this, we will first determine the molecular
mechanisms of action of SMIC1 in treatment of glioblastoma cells. In particular, we will examine how SMIC1
treatment induces the ubiquitination and degradation of SUMO1 protein and abolishes SUMO1 conjugation
pathway in human glioblastoma cells. Next, we will examine the bioactivity and pharmacodynamics of SMIC1
in comparison with CDK4/6 inhibitors in genetically heterogenous glioblastoma cells and thus determine why
SMIC1 treatment can overcome the resistance of RB1 deletion and mutation. Finally, we will evaluate the
therapeutic efficacy of SMIC1 using the cancer stem cell cultures and xenograft models generated from
patients' glioblastoma tissues. Upon completion, this project will lead to the genesis of a new class anticancer
drug for clinical treatment of glioblastoma patients.
我们的最终目标是开发新的有效治疗胶质母细胞瘤的方法,胶质母细胞瘤是最常见和最致命的
人类脑癌。为了实现这一目标,我们建议将SUMO1抑制化合物(SMIC1)开发为
一种治疗胶质母细胞瘤的抗癌新药。SUMO1(小泛素样修饰物-1)是一种小型调节性蛋白
通过酶反应与底物蛋白质相连的蛋白质。其底物的SUMO1偶联
蛋白质控制底物蛋白质的细胞功能。在我们最近的工作中,我们揭示了SUMO1
结合途径在胶质母细胞瘤中过度活跃,并推动肿瘤的进展。为了瞄准这条路径,
我们已经建立了基于胶质母细胞瘤细胞的SUMO1药物筛选方法,并从
NCI的可用药化合物图书馆。在SMIC1作为抗癌药物的临床前开发工作中,
我们遵循了fda的指南,对新的抗癌药物进行了非临床评价并进行了毒性试验。
和SMIC1的药代动力学(PK),表明SMIC1具有可接受的安全裕度和
在动物身上有可吸毒的PK特征。在全身给药中,SMIC1可以通过以下途径迅速传递到大脑
血脑屏障(BBB),并有效地抑制胶质母细胞瘤异种移植生长。
在寻找靶蛋白的过程中,我们发现细胞周期蛋白依赖的激酶-6(Cdk6)是两者的底物。
SUMO1和泛素(UB)。SUMO1-CDK6结合阻断CDK6泛素化及UB介导的
降解,从而稳定CDK6激酶,通过磷酸化视网膜母细胞瘤来驱动细胞生长
蛋白-1(RB1);因此,SMIC1处理阻断了SUMO1-CDK6的结合,并消除了CDK6-RB1途径。
另一方面,针对CDK4/6-RB1途径的CDK4/6抑制剂已经被开发出来,它们现在正在
接受癌症治疗的临床医生。Rb1缺失和突变发生在大约11%的胶质母细胞瘤中,并导致
肿瘤对CDK4/6抑制剂的耐药性。相反,我们已经证明SMIC1可以克服阻力
通过抑制各种SUMO1底物蛋白。这项建议的目标是将SMIC1发展为
治疗胶质母细胞瘤的抗癌新药。为了实现这一点,我们将首先确定分子
SMIC1在胶质母细胞瘤细胞治疗中的作用机制我们将特别研究SMIC1如何
治疗诱导SUMO1蛋白泛素化和降解并取消SUMO1结合
人脑胶质母细胞瘤细胞中的通路。接下来,我们将研究SMIC1的生物活性和药效学
与CDK4/6抑制剂在基因异质性胶质母细胞瘤细胞中的比较,从而确定为什么
SMIC1处理可以克服RB1缺失和突变的抗性。最后,我们将评估
SMIC1在肿瘤干细胞培养和异种移植模型中的治疗作用
患者的胶质母细胞瘤组织。该项目完成后,将催生一种新的抗癌药物。
用于临床治疗胶质母细胞瘤患者的药物。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.
- DOI:10.1126/scitranslmed.abh1486
- 发表时间:2021-10-13
- 期刊:
- 影响因子:17.1
- 作者:Bellail, Anita C.;Jin, Hong Ri;Lo, Ho-Yin;Jung, Sung Han;Hamdouchi, Chafiq;Kim, Daeho;Higgins, Ryan K.;Blanck, Maximilian;le Sage, Carlos;Cross, Benedict C. S.;Li, Jing;Mosley, Amber L.;Wijeratne, Aruna B.;Jiang, Wen;Ghosh, Manali;Zhao, Yin Quan;Hauck, Paula M.;Shekhar, Anantha;Hao, Chunhai
- 通讯作者:Hao, Chunhai
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CHUNHAI Charlie HAO其他文献
CHUNHAI Charlie HAO的其他文献
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{{ truncateString('CHUNHAI Charlie HAO', 18)}}的其他基金
Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy.
开发用于胶质母细胞瘤治疗的 BBB 渗透性 SUMO1 小分子降解剂。
- 批准号:
10420361 - 财政年份:2022
- 资助金额:
$ 38.01万 - 项目类别:
Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy.
开发用于胶质母细胞瘤治疗的 BBB 渗透性 SUMO1 小分子降解剂。
- 批准号:
10580075 - 财政年份:2022
- 资助金额:
$ 38.01万 - 项目类别:
Molecular mechanisms of TRAIL resistance in glioblastoma
胶质母细胞瘤TRAIL耐药的分子机制
- 批准号:
7743791 - 财政年份:2009
- 资助金额:
$ 38.01万 - 项目类别:
Molecular mechanisms of TRAIL resistance in glioblastoma
胶质母细胞瘤TRAIL耐药的分子机制
- 批准号:
7583094 - 财政年份:2009
- 资助金额:
$ 38.01万 - 项目类别:
Molecular mechanisms of TRAIL resistance in glioblastoma
胶质母细胞瘤TRAIL耐药的分子机制
- 批准号:
8403805 - 财政年份:2009
- 资助金额:
$ 38.01万 - 项目类别:
Molecular mechanisms of TRAIL resistance in glioblastoma
胶质母细胞瘤TRAIL耐药的分子机制
- 批准号:
8206632 - 财政年份:2009
- 资助金额:
$ 38.01万 - 项目类别:
Molecular mechanisms of TRAIL resistance in glioblastoma
胶质母细胞瘤TRAIL耐药的分子机制
- 批准号:
8009820 - 财政年份:2009
- 资助金额:
$ 38.01万 - 项目类别:
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