Targeting dynamic palmitoylation of TEAD transcription factors
靶向 TEAD 转录因子的动态棕榈酰化
基本信息
- 批准号:10599147
- 负责人:
- 金额:$ 53.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:BindingBiologyCancer ModelCancer cell lineCarbonCell ProliferationCell SurvivalChemicalsComplexDNA Binding DomainDependenceDevelopmentDrug KineticsEncyclopediasEnzymesFatty AcidsGenetic TranscriptionGenetically Engineered MouseGrowthHumanHydrolaseHydrophobicityIn VitroKnowledgeLATS1 geneLipid BindingLiverMalignant NeoplasmsMalignant neoplasm of liverMediatingOncogenicOncoproteinsOrgan SizeOutputPalmitatesPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPhosphorylationPhosphotransferasesPhysiologicalPlayPost-Translational Protein ProcessingProcessPropertyProteinsRegulationReportingRoleSignal TransductionStructureSystemTestingTissuesTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationTumor SuppressionVerteporfinXenograft Modelanalogcancer cellcancer therapychemoproteomicsdrug discoveryfatty acylationimprovedin vivoin vivo Modelinhibitormalignant breast neoplasmmouse modelnovelnovel strategiesnovel therapeutic interventionpalmitoylationpharmacologicprogramssmall moleculesmall molecule inhibitortherapeutically effectivetooltranscription factortumorigenesis
项目摘要
Deregulation of Hippo–YAP signaling is implicated in diverse human cancers. TEAD
transcription factors bind to the transcription co-activators YAP/TAZ, and control the
transcriptional output of the Hippo pathway. However, it remains difficult to directly target
TEAD–YAP by small molecules. We previously discovered that TEADs possess intrinsic
“enzyme-like” activities and undergo autopalmitoylation (16-carbon fatty acylation).
Palmitoylation is critical for TEAD protein stability and transcriptional activation. We recently
discovered that ABHD1 is a novel depalmitoylase regulating TEADs. Loss of ABHD1 in cancers
might lead to sustained TEAD palmitoylation and activation of TEAD–YAP. In addition, we
identified MGH-CP1 as novel chemical inhibitor of TEAD palmitoylation, providing a
pharmacological tool to suppress TEAD–YAP activates in cancers.
Our specific aims of this proposal include: (1) to investigate the role of ABHD1 in regulation of
TEAD depalmitoylation; (2) To optimize MGH-CP1 and develop potent and selective TEAD
inhibitors. (3) To target TEAD–YAP transcriptional complex in vitro and in vivo using
pharmacological tools.
Hippo-YAP 信号传导的失调与多种人类癌症有关。 TEAD
转录因子与转录共激活因子 YAP/TAZ 结合,并控制
Hippo 途径的转录输出。但仍难以直接瞄准
小分子TEAD-YAP。我们之前发现 TEAD 具有内在的
“酶样”活性并进行自棕榈酰化(16-碳脂肪酰化)。
棕榈酰化对于 TEAD 蛋白稳定性和转录激活至关重要。我们最近
发现 ABHD1 是一种调节 TEAD 的新型去棕榈酰化酶。癌症中 ABHD1 的缺失
可能会导致 TEAD 棕榈酰化和 TEAD-YAP 的持续激活。此外,我们
确定 MGH-CP1 是 TEAD 棕榈酰化的新型化学抑制剂,提供了
抑制癌症中 TEAD-YAP 激活的药理学工具。
我们该提案的具体目标包括:(1)研究ABHD1在调节中的作用
TEAD 去棕榈酰化; (2) 优化MGH-CP1并开发强效选择性TEAD
抑制剂。 (3) 在体外和体内靶向 TEAD-YAP 转录复合物
药理学工具。
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(0)
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Junhao Mao其他文献
Junhao Mao的其他文献
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{{ truncateString('Junhao Mao', 18)}}的其他基金
Mechanism of YAP/TAZ crosstalk with Wnt signaling
YAP/TAZ 与 Wnt 信号的串扰机制
- 批准号:
10328901 - 财政年份:2021
- 资助金额:
$ 53.7万 - 项目类别:
Mechanism of YAP/TAZ crosstalk with Wnt signaling
YAP/TAZ 与 Wnt 信号的串扰机制
- 批准号:
10552565 - 财政年份:2021
- 资助金额:
$ 53.7万 - 项目类别:
Dependence for TEAD transcription factors in intestinal development and polyposis
肠道发育和息肉病中 TEAD 转录因子的依赖性
- 批准号:
10100436 - 财政年份:2020
- 资助金额:
$ 53.7万 - 项目类别:
Dependence for TEAD transcription factors in intestinal development and polyposis
肠道发育和息肉病中 TEAD 转录因子的依赖性
- 批准号:
10264875 - 财政年份:2020
- 资助金额:
$ 53.7万 - 项目类别:
Dependence for TEAD transcription factors in intestinal development and polyposis
肠道发育和息肉病中 TEAD 转录因子的依赖性
- 批准号:
10455713 - 财政年份:2020
- 资助金额:
$ 53.7万 - 项目类别:
Dependence for TEAD transcription factors in intestinal development and polyposis
肠道发育和息肉病中 TEAD 转录因子的依赖性
- 批准号:
10671636 - 财政年份:2020
- 资助金额:
$ 53.7万 - 项目类别:
Targeting dynamic palmitoylation of TEAD transcription factors
靶向 TEAD 转录因子的动态棕榈酰化
- 批准号:
10373011 - 财政年份:2019
- 资助金额:
$ 53.7万 - 项目类别:
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