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信号转导的失调与多种人类癌症有关。TEAD
转录因子与转录辅激活因子雅普/TAZ结合,并控制转录因子的表达。
Hippo途径的转录输出。然而,仍然难以直接针对
TEAD-YAP由小分子。我们以前发现TEAD具有内在的
这些酶具有“酶样”活性并经历自棕榈酰化(16-碳脂肪酰化)。
棕榈酰化对于TEAD蛋白的稳定性和转录激活是至关重要的。我们最近
发现ABHD 1是一种新的调节TEAD的脱棕榈酰酶。癌症中ABHD 1的缺失
可能导致持续的TEAD棕榈酰化和TEAD-YAP的激活。另外我们
鉴定MGH-CP 1为TEAD棕榈酰化的新型化学抑制剂,
在癌症中抑制TEAD-YAP激活的药理学工具。
本研究的具体目的包括:(1)研究ABHD 1在调节
TEAD脱棕榈酰化;(2)优化MGH-CP 1,开发高效、选择性TEAD
抑制剂的(3)为了在体外和体内靶向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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