1. Academic Validation
  2. The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma

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. 2020 Dec 1;10(12):4399-4415.
Ayumi Kaneda 1 2 Toshihiro Seike 1 Tomohiro Danjo 1 Takahiro Nakajima 1 Nobumasa Otsubo 1 Daisuke Yamaguchi 1 Yoshiro Tsuji 1 Kaori Hamaguchi 1 Mai Yasunaga 1 Yoichi Nishiya 1 Michihiko Suzuki 1 Jun-Ichi Saito 1 Rie Yatsunami 2 Satoshi Nakamura 2 3 Yoshitaka Sekido 4 5 Kiyotoshi Mori 1
Affiliations

Affiliations

  • 1 R&D Division, Kyowa Kirin Co., Ltd Shizuoka, Japan.
  • 2 School of Life Science and Technology, Tokyo Institute of Technology Yokohama, Japan.
  • 3 National Institute of Technology, Numazu College Shizuoka, Japan.
  • 4 Division of Cancer Biology, Aichi Cancer Center Research Institute Nagoya, Japan.
  • 5 Division of Molecular and Cellular Oncology, Nagoya University Graduate School of Medicine Nagoya, Japan.
PMID: 33415007
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.

Keywords

Anti-cancer agent; Hippo pathway; covalent inhibitor; mesothelioma; transcriptional enhanced associate domain (TEAD).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138565
    99.27%, YAP1/TAZ-TEAD抑制剂
    YAP