Discovery of Clinical Candidate IAG933, a Potent YAP-TEAD PPI Disrupter

The interaction of transcriptional enhanced associate
domain (TEAD)
and transcriptional coactivator yes-associated protein (YAP) mediates
oncogenic functions downstream of the Hippo pathway. In this report,
we outline our efforts to find a potent inhibitor of this protein–protein
interaction with suitable properties for clinical evaluation. We detail
the medicinal chemistry program that led to the discovery of IAG933,
an inhibitor with a balanced ADME profile, enabling its evaluation
as a potential treatment option in clinical settings.

转录增强关联域（transcriptional enhanced associate domain，TEAD）与转录共激活因子yes相关蛋白（transcriptional coactivator yes-associated protein，YAP）的相互作用，介导了河马信号通路（Hippo pathway）下游的致癌功能。本报告中，我们详述了为寻找具备适宜临床评价特性的该蛋白质-蛋白质相互作用强效抑制剂所开展的研究工作。我们详细介绍了促成IAG933发现的药物化学研究项目——IAG933是一种具有均衡ADME特性的抑制剂，使其可作为潜在治疗方案在临床环境中开展评估。