Abstract：
The Hippo pathway, which is key in organ morphogenesis, is frequently deregulated in cancer. The TEAD (TEA domain family member) transcription factors are the most distal elements of this pathway, and their activity is regulated by proteins such as YAP (Yes-associated protein). The identification of inhibitors of the YAP:TEAD interaction is one approach to develop novel anticancer drugs: the first clinical candidate (IAG933) preventing the association between these two proteins by direct competition has just been reported. The discovery of this molecule was particularly challenging because the interface between these two proteins is large (~ 3500 Å2 buried in complex formation) and made up of distinct contact areas. The most critical of these involves an omega-loop (Ω-loop), a secondary structure element rarely found in protein-protein interactions. This review summarizes how the knowledge gained from structure-function studies of the interaction between the Ω-loop of YAP and TEAD was used to devise the strategy to identify potent low-molecular weight compounds that show a pronounced anti-tumor effect.
摘要：
河马之路,这是器官形态发生的关键，经常在癌症中失调。TEAD(TEA结构域家族成员)转录因子是该通路的最远端元件,它们的活性受YAP（Yes相关蛋白）等蛋白质的调节。YAP：TEAD相互作用的抑制剂的鉴定是开发新的抗癌药物的一种方法：第一个临床候选药物（IAG933）通过直接竞争防止这两种蛋白质之间的关联刚刚被报道。该分子的发现特别具有挑战性，因为这两种蛋白质之间的界面很大（〜3500µ2埋在复合物形成中），并且由不同的接触区域组成。其中最关键的涉及欧米茄环路（Ω环路），在蛋白质-蛋白质相互作用中很少发现的二级结构元件。这篇综述总结了如何从YAP和TEAD的Ω环之间的相互作用的结构-功能研究中获得的知识用于设计策略，以鉴定具有显着的抗肿瘤作用的有效低分子量化合物。
