Targeting dynamic palmitoylation of TEAD transcription factors

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

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.