Targeting dynamic palmitoylation of TEAD transcription factors

河马-YAP信号的解除调控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，控制 河马途径的转录输出。然而，要直接瞄准目标仍然困难。 小分子的Tead-Yap。我们之前发现Tead具有内在的 “类酶”活性，并经历自动转氨酰化(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ABHD1是一种新的调节Teads的脱氨酶。ABHD1基因在癌症中的缺失 可能导致持续的Tead棕榈酰化和Tead-Yap的激活。此外，我们 确定MGH-CP1为Tead棕榈酰化的新型化学抑制剂，提供了一种 抑制癌症中tead-yap激活的药理工具。 我们这项建议的具体目标包括：(1)调查ABHD1在调节 (2)优化MGH-CP1，开发高效、选择性的TEAD 抑制剂。(3)体外和体内靶向tead-Yap转录复合体 药理工具。

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.