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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：
Junhao Mao
金额：
$ 53.7万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
https://reporter.nih.gov/project-details/10373011
关键词：
Binding Biology Cancer Model Cancer cell line Carbon Cell Proliferation Cell Survival Chemicals Complex Crystallization DNA Binding Domain Dependence Development Drug Kinetics Encyclopedias Enzymes Fatty Acids Genetic Transcription Genetically Engineered Mouse Human Hydrolase Hydrophobicity In Vitro Knowledge LATS1 gene Lead Lipid Binding Liver Malignant Neoplasms Malignant neoplasm of liver Mediating Oncogenic Oncoproteins Organ Size Output Palmitates Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Physiological Play Post-Translational Protein Processing Process Property Proteins Regulation Reporting Role Signal Transduction Structure System Testing Tissues Transcription Coactivator Transcriptional Activation Transcriptional Regulation Tumor Suppression Verteporfin Xenograft Model analog base cancer cell cancer therapy chemoproteomics drug discovery fatty acylation improved in vivo in vivo Model inhibitor malignant breast neoplasm novel novel strategies novel therapeutic intervention palmitoylation programs small molecule small molecule inhibitor therapeutically effective tool transcription factor tumorigenesis

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