Pan-Transcriptional\nEnhanced Associated Domain Palmitoylation\nPocket Covalent Inhibitor

In the Hippo signaling pathway, the palmitoylated transcriptional\nenhanced associated domain (TEAD) protein interacts with the coactivator\nYes-associated protein/PDZ-binding motif, leading to transcriptional\nupregulation of oncogenes such as Ctgf and Cyr61. Consequently, targeting\nthe palmitoylation sites of TEAD has emerged as a promising strategy\nfor treating TEAD-dependent cancers. Compound <b>1</b> was identified\nusing a structure-based drug design approach, leveraging the molecular\ninsights gained from the known TEAD palmitoylation site inhibitor,\nK-975. Optimization of the initial hit compound resulted in the development\nof compound <b>3</b>, a covalent pan-TEAD inhibitor characterized\nby high potency and oral bioavailability.