SUMO Modification and Cancer Therapy
SUMO Modification and Cancer Therapy
批准号:
10396642
负责人:
Yuan Chen
金额:
$50.23万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-01 至 2026-04-30
关键词:
AddressAnimal ModelAntibodiesBiochemicalBiologicalBiological AssayCD8-Positive T-LymphocytesCancer PatientCellsCellular AssayClinical ResearchClinical TrialsColorectal CancerComplexCrystallizationDendritic CellsDrug KineticsDrug resistanceEnzyme InhibitionEnzyme Inhibitor DrugsEnzyme KineticsEnzymesFDA approvedFundingGoalsHumanImmuneImmunomodulatorsImmunotherapyIn VitroInterferon Type IInterferonsIntravenous infusion proceduresInvestigationKnowledgeLeadLifeMalignant NeoplasmsMediatingMedicalMethodsModelingModificationMolecularMultienzyme ComplexesMutationOncogenesPathway interactionsPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePhasePhase I/II Clinical TrialPost-Translational Protein ProcessingProgress ReportsPropertyProteinsPublishingRegulationResistanceSiteSolid NeoplasmStereoisomerStructureStructure-Activity RelationshipSumoylation PathwayT cell responseTherapeuticTumor ImmunityUbiquitinUbiquitinationUnited States National Institutes of Healthanalogcancer drug resistancecancer immunotherapycancer therapydrug discoverydrug metabolismexperiencefollow-uphigh throughput screeninghuman diseaseimprovedin vivoinhibitorinnovationinsightinterdisciplinary approachlead optimizationneoplastic cellnovelresistance mutationresponsesmall moleculetargeted treatmenttherapeutic developmenttherapeutic targettumor
中文摘要
许多催化泛素样 (Ubl) 修饰的酶已被确定为
无法治愈的危及生命的人类疾病的治疗发展。然而,乌布尔
FDA 批准的药物很难解决修饰问题,凸显了巨大的潜力
利用这种类型的翻译后修饰来解决未满足的医疗需求。
Ubl 与靶蛋白的结合是通过激活 Ubl 的 C 末端开始的,这是一个步骤
由通常称为活化酶或E1的酶催化。几种E1酶,
包括 SUMO 激活酶 (SAE),已被验证为治疗靶点
动物模型和早期临床研究。我们最近发现了一个保守的
SAE 上的神秘位点提供了一种范式转换的变构方法来抑制 Ubl
激活酶。在下一个资助期内,我们将进一步阐明其机制
结构-活性关系。此外,我们将验证变构抑制
我们发现的方法可降低针对 Ubl 激活的癌症耐药性
酶。此外,我们将定义 SUMOylation 的分子机制
调节 I 型 IFN 表达并验证 SAE 抑制是一种有效的方法
诱导免疫冷性结直肠癌的抗肿瘤免疫力。拟议的研究建立
关于我们在上一个资助周期中的科学进展以及我们20多年来的科学进展
研究 SUMOylation 的经验。拟议的研究预计将产生长期
持久的影响将刺激针对 Ubl 的治疗开发和创新
为对免疫冷肿瘤没有反应的新免疫治疗策略
当前的免疫疗法和未满足的需求很高,例如结直肠癌。
英文摘要
Many enzymes catalyzing ubiquitin-like (Ubl) modifications have been identified as targets for
the therapeutic development of life-threatening human diseases that lack a cure. However, Ubl
modifications are poorly addressed by FDA approved drugs, highlighting the immense potential
to exploit this type of post-translational modification to address unmet medical needs.
Conjugation of Ubls to target proteins begins by activation of the C-terminus of a Ubl, a step
catalyzed by enzymes generally known as activating enzyme or E1. Several E1 enzymes,
including the SUMO-activating enzyme (SAE), have been validated as therapeutic targets by
animal models and by early phase clinical studies. Our recent discovery of a conserved
cryptic site on the SAE provides a paradigm-shifting allosteric approach to inhibit Ubl
activating enzymes. In the next funding period, we will further elucidate the mechanism of
the structure-activity relationship. Additionally, we will validate that the allosteric inhibition
approach we discovered reduces cancer drug resistance for targeting Ubl activating
enzymes. Furthermore, we will define the molecular mechanism of how SUMOylation
regulates type I IFN expression and validate that SAE inhibition is an effective approach to
induce anti-tumor immunity for immune cold colorectal cancers. The proposed studies build
on our scientific progress in the previous funding cycle and our more than 20-year
experience in studying SUMOylation. The proposed studies are expected to result in long-
lasting impacts that will spur innovation in targeting Ubl for therapeutic development and
result in new immune therapeutic strategies for immune cold tumors that do not respond to
current immune therapies and are high unmet needs, such as colorectal cancers.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Surgical Oncologists as Scientists (SOAS) Training Program
-
批准号:10555596
-
项目类别:
-
资助金额:$17.03万
-
财政年份:2023
-
负责人:Yuan Chen
-
依托单位:
SUMO Modification and Cancer Therapy
-
批准号:10629198
-
项目类别:
-
资助金额:$51.26万
-
财政年份:2021
-
负责人:Yuan Chen
-
依托单位:
K-Ras sumoylation in cell proliferation and transformation
-
批准号:9402787
-
项目类别:
-
资助金额:$51.49万
-
财政年份:2017
-
负责人:Yuan Chen
-
依托单位:
K-Ras sumoylation in cell proliferation and transformation
-
批准号:9924462
-
项目类别:
-
资助金额:$49.75万
-
财政年份:2017
-
负责人:Yuan Chen
-
依托单位:
Targeting c-Myc and Proteasome Inhibitor Resistance in Multiple Myeloma
-
批准号:9942394
-
项目类别:
-
资助金额:$53.64万
-
财政年份:2017
-
负责人:Yuan Chen
-
依托单位:
SENP:Conformational Dynamics and Inhibition by Small Molecules
-
批准号:8287411
-
项目类别:
-
资助金额:$38.43万
-
财政年份:2012
-
负责人:Yuan Chen
-
依托单位:
SENP:Conformational Dynamics and Inhibition by Small Molecules
-
批准号:8454447
-
项目类别:
-
资助金额:$37.09万
-
财政年份:2012
-
负责人:Yuan Chen
-
依托单位:
SENP:Conformational Dynamics and Inhibition by Small Molecules
-
批准号:8649059
-
项目类别:
-
资助金额:$49.18万
-
财政年份:2012
-
负责人:Yuan Chen
-
依托单位:
SENP:Conformational Dynamics and Inhibition by Small Molecules
-
批准号:8829872
-
项目类别:
-
资助金额:$38.43万
-
财政年份:2012
-
负责人:Yuan Chen
-
依托单位:
High Throughput Assays to Identify Inhibitors of SUMO-mediated Protein-Protein In
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批准号:8413730
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项目类别:
-
资助金额:$4.15万
-
财政年份:2009
-
负责人:Yuan Chen
-
依托单位:
The Enzymatic Pathway of a Ubiquitin-Like Modification
-
批准号:7939059
-
项目类别:
-
资助金额:$5.54万
-
财政年份:2009
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and cancer therapy
-
批准号:8975778
-
项目类别:
-
资助金额:$42.57万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and DNA damage response in cancer therapy
-
批准号:8068284
-
项目类别:
-
资助金额:$41.08万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and cancer therapy
-
批准号:8439300
-
项目类别:
-
资助金额:$41.79万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
A high throughput screening assay for the identification of SUMOylation inhibitor
-
批准号:7563063
-
项目类别:
-
资助金额:$2.5万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and DNA damage response in cancer therapy
-
批准号:8134609
-
项目类别:
-
资助金额:$5.48万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and DNA damage response in cancer therapy
-
批准号:7472808
-
项目类别:
-
资助金额:$33.3万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and cancer therapy
-
批准号:8595315
-
项目类别:
-
资助金额:$32.46万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and cancer therapy
-
批准号:8754756
-
项目类别:
-
资助金额:$8.56万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
SUMO modification and DNA damage response in cancer therapy
-
批准号:7797685
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项目类别:
-
资助金额:$39.77万
-
财政年份:2008
-
负责人:Yuan Chen
-
依托单位:
海外基金