7CNL

Crystal structure of TEAD3 in complex with VT105

Summary for 7CNL

• Entry DOI: 10.2210/pdb7cnl/pdb
• Descriptor: Transcriptional enhancer factor TEF-5, N-oxidanyltetradecanamide, PHOSPHATE ION, ... (7 entities in total)
• Functional Keywords: tead, inhibitor, palmitoylation, hippo pathway, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 103816.69

Authors

Tang, T.T.,Konradi, A.W. (deposition date: 2020-08-01, release date: 2021-04-28, Last modification date: 2023-11-29)

Primary citation

Tang, T.T.,Konradi, A.W.,Feng, Y.,Peng, X.,Ma, M.,Li, J.,Yu, F.X.,Guan, K.L.,Post, L.
Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2 -deficient Mesothelioma.
Mol.Cancer Ther., 20:986-998, 2021

PubMed Abstract: Mutations in the neurofibromatosis type 2 () gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit -deficient mesothelioma cell proliferation and growth of subcutaneous tumor xenografts These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.

PubMed: 33850002
DOI: 10.1158/1535-7163.MCT-20-0717

Experimental method

X-RAY DIFFRACTION (2.6 Å)