7CMM

Crystal structure of TEAD1-YBD in complex with K-975

Summary for 7CMM

• Entry DOI: 10.2210/pdb7cmm/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, N-[3-(4-chloranylphenoxy)-4-methyl-phenyl]propanamide (3 entities in total)
• Functional Keywords: transcriptional enhancer factor tef-1, tead, tead1, yap binding domain, ybd, inhibitor, covalent binder, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 107439.68

Authors

Tsuji, Y.,Suzuki, M.,Yasunaga, M.,Hamguchi, K.,Saito, J. (deposition date: 2020-07-28, release date: 2021-02-03, Last modification date: 2024-10-16)

Primary citation

Kaneda, A.,Seike, T.,Danjo, T.,Nakajima, T.,Otsubo, N.,Yamaguchi, D.,Tsuji, Y.,Hamaguchi, K.,Yasunaga, M.,Nishiya, Y.,Suzuki, M.,Saito, J.I.,Yatsunami, R.,Nakamura, S.,Sekido, Y.,Mori, K.
The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma.
Am J Cancer Res, 10:4399-4415, 2020

PubMed Abstract: The Hippo signaling pathway regulates cell fate and organ development. In the Hippo pathway, transcriptional enhanced associate domain (TEAD) which is a transcription factor is activated by forming a complex with yes-associated protein 1 (YAP1) or transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1). Hyper-activation of YAP1/TAZ, leading to the activation of TEAD, has been reported in many cancers, including malignant pleural mesothelioma (MPM). Therefore, the YAP1/TAZ-TEAD complex is considered a novel therapeutic target for cancer treatment. However, few reports have described YAP1/TAZ-TEAD inhibitors, and their efficacy and selectivity are poor. In this study, we performed a high-throughput screening of a neurofibromin 2 (NF2)-deficient MPM cell line and a large tumor suppressor kinase 1/2 (LATS1/2)-deficient non-small-cell lung cancer cell line using a transcriptional reporter assay. After screening and optimization, K-975 was successfully identified as a potent inhibitor of YAP1/TAZ-TEAD signaling. X-ray crystallography revealed that K-975 was covalently bound to an internal cysteine residue located in the palmitate-binding pocket of TEAD. K-975 had a strong inhibitory effect against protein-protein interactions between YAP1/TAZ and TEAD in cell-free and cell-based assays. Furthermore, K-975 potently inhibited the proliferation of NF2-non-expressing MPM cell lines compared with NF2-expressing MPM cell lines. K-975 also suppressed tumor growth and provided significant survival benefit in MPM xenograft models. These findings indicate that K-975 is a strong and selective TEAD inhibitor with the potential to become an effective drug candidate for MPM therapy.

PubMed: 33415007

Experimental method

X-RAY DIFFRACTION (3.5 Å)