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Crystal structure of TEAD3 YAP binding domain with compound 3
Structural highlights
FunctionTEAD3_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer.[1] [2] Publication Abstract from PubMedIn 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. Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor.,Kim J, Kim H, Kim J, Cho SY, Moon S, Yoo Y, Kim H, Kim JK, Jeon H, Namkung W, Han G, No KT J Med Chem. 2024 Nov 14;67(21):18957-18968. doi: 10.1021/acs.jmedchem.4c01393. , Epub 2024 Nov 2. PMID:39487823[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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