Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor

In the Hippo signaling pathway, the palmitoylated transcriptional
enhanced associated domain (TEAD) protein interacts with the coactivator
Yes-associated protein/PDZ-binding motif, leading to transcriptional
upregulation of oncogenes such as Ctgf and Cyr61. Consequently, targeting
the palmitoylation sites of TEAD has emerged as a promising strategy
for treating TEAD-dependent cancers. Compound 1 was identified
using a structure-based drug design approach, leveraging the molecular
insights gained from the known TEAD palmitoylation site inhibitor,
K-975. Optimization of the initial hit compound resulted in the development
of compound 3, a covalent pan-TEAD inhibitor characterized
by high potency and oral bioavailability.