Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor

作者：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 · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01393 · 被引用次数：12 · 研究领域：Cancer-related gene regulation、Hippo pathway signaling and YAP/TAZ、Ubiquitin and proteasome pathways

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.