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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：
10599147
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/10599147
关键词：
Binding Biology Cancer Model Cancer cell line Carbon Cell Proliferation Cell Survival Chemicals Complex DNA Binding Domain Dependence Development Drug Kinetics Encyclopedias Enzymes Fatty Acids Genetic Transcription Genetically Engineered Mouse Growth Human Hydrolase Hydrophobicity In Vitro Knowledge LATS1 gene Lipid Binding Liver Malignant Neoplasms Malignant neoplasm of liver Mediating Oncogenic Oncoproteins Organ Size Output Palmitates Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations 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 cancer cell cancer therapy chemoproteomics drug discovery fatty acylation improved in vivo in vivo Model inhibitor malignant breast neoplasm mouse model novel novel strategies novel therapeutic intervention palmitoylation pharmacologic 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。