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:10373011
- 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 SurvivalChemicalsComplexCrystallizationDNA Binding DomainDependenceDevelopmentDrug KineticsEncyclopediasEnzymesFatty AcidsGenetic TranscriptionGenetically Engineered MouseHumanHydrolaseHydrophobicityIn VitroKnowledgeLATS1 geneLeadLipid BindingLiverMalignant NeoplasmsMalignant neoplasm of liverMediatingOncogenicOncoproteinsOrgan SizeOutputPalmitatesPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhosphorylationPhosphotransferasesPhysiologicalPlayPost-Translational Protein ProcessingProcessPropertyProteinsRegulationReportingRoleSignal TransductionStructureSystemTestingTissuesTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationTumor SuppressionVerteporfinXenograft Modelanalogbasecancer cellcancer therapychemoproteomicsdrug discoveryfatty acylationimprovedin vivoin vivo Modelinhibitormalignant breast neoplasmnovelnovel strategiesnovel therapeutic interventionpalmitoylationprogramssmall 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:
10599147 - 财政年份:2019
- 资助金额:
$ 53.7万 - 项目类别:
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