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针对胶质母细胞瘤的新颖有效的治疗方法,胶质母细胞瘤是最常见和致命的疾病
人类脑癌。为了实现这一目标,我们建议开发 SUMO1 抑制化合物(SMIC1):
一种用于治疗胶质母细胞瘤的新抗癌药物。 SUMO1(小泛素样修饰剂-1)是一种小型调节剂
通过酶促反应与底物蛋白连接的蛋白质。 SUMO1 与其底物的结合
蛋白质控制底物蛋白质的细胞功能。在我们最近的工作中,我们发现 SUMO1
接合途径在胶质母细胞瘤中过度活跃并驱动癌症进展。为了瞄准这条途径,
我们开发了基于胶质母细胞瘤细胞的 SUMO1 检测方法用于药物筛选,并从其中鉴定出 SMIC1
NCI 可药物化合物库。在SMIC1作为抗癌药物的临床前开发的努力中,
我们遵循FDA关于新抗癌药物非临床评价的指南并测试了毒性
和 SMIC1 的药代动力学(PK),并证明 SMIC1 具有可接受的安全裕度和
动物体内可药物的 PK 特征。在全身给药中,SMIC1可以通过
血脑屏障(BBB)并有效抑制胶质母细胞瘤异种移植物的生长。
在寻找靶蛋白时,我们发现细胞周期蛋白依赖性激酶 6 (CDK6) 是两者的底物
SUMO1 和泛素 (UB)。 SUMO1-CDK6 缀合可阻断 CDK6 泛素化和 UB 介导的
降解,从而稳定 CDK6 激酶,通过视网膜母细胞瘤磷酸化驱动细胞生长
蛋白质-1 (RB1);因此,SMIC1 治疗可阻断 SUMO1-CDK6 结合并消除 CDK6-RB1 通路。
另一方面,针对CDK4/6-RB1通路的CDK4/6抑制剂已被开发出来,现已上市
在临床上用于癌症治疗。约 11% 的胶质母细胞瘤中发生 RB1 缺失和突变,并导致
癌症对 CDK4/6 抑制剂的耐药性。相比之下,我们已经证明 SMIC1 可以克服阻力
通过抑制各种 SUMO1 底物蛋白。本提案的目标是将 SMIC1 发展为
一种用于治疗胶质母细胞瘤的新抗癌药物。为了实现这一点,我们首先要确定分子
SMIC1治疗胶质母细胞瘤细胞的作用机制。我们将特别研究 SMIC1 如何
治疗诱导 SUMO1 蛋白泛素化和降解并消除 SUMO1 结合
人胶质母细胞瘤细胞中的途径。接下来我们将考察SMIC1的生物活性和药效学
与遗传异质性胶质母细胞瘤细胞中的 CDK4/6 抑制剂进行比较,从而确定原因
SMIC1治疗可以克服RB1缺失和突变的抵抗力。最后,我们将评估
使用癌症干细胞培养物和异种移植模型生成的 SMIC1 的治疗效果
患者的胶质母细胞瘤组织。完成后,该项目将导致新型抗癌药物的诞生
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:
8009820 - 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:
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