TY - JOUR
T1 - Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor
AU - Kim, Jinhyuk
AU - Kim, Hadong
AU - Kim, Jongwan
AU - Cho, Seon Yeon
AU - Moon, Sungho
AU - Yoo, Youngki
AU - Kim, Hanseong
AU - Kim, Jin Kwan
AU - Jeon, Hyejin
AU - Namkung, Wan
AU - Han, Gyoonhee
AU - No, Kyoung Tai
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/11/14
Y1 - 2024/11/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.4c01393
DO - 10.1021/acs.jmedchem.4c01393
M3 - Article
C2 - 39487823
AN - SCOPUS:85208750868
SN - 0022-2623
VL - 67
SP - 18957
EP - 18968
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -