Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor
J S Kim, Hadong Kim, Jongwan Kim, Seon Yeon Cho, Sungho Moon, Youngki Yoo, Hanseong Kim, Jinkwan Kim, Hyejin Jeon, W. Namkung, Gyoonhee Han, Kyoung Tai No
Abstract
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.