@article{57689f7f688a4be5a0a72bbe617c86e4,
title = "A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins",
abstract = "Although treatments for allergic diseases have improved, side effects and treatment resistance remain as challenges. New therapeutic drugs for allergic diseases are urgently required. Thymic stromal lymphopoietin (TSLP) is a cytokine target for prevention and treatment of allergic diseases. Since TSLP is produced from epithelial cells in allergic diseases, TSLP inhibitors may be new anti-allergic drugs. We previously identified a new inhibitor of TSLP production, named 16D10. However, its target of action remained unclarified. In this study, we found proteins binding to 16D10 from 24,000 human protein arrays by AlphaScreen-based high-throughput screening and identified bromodomain and extra-terminal (BET) family proteins as targets. We also clarified the detailed mode of interaction between 16D10 and a BET family protein using X-ray crystallography. Furthermore, we confirmed that inhibitors of BET family proteins suppressed TSLP induction and IL-33 and IL-36γ expression in both mouse and human keratinocyte cell lines. Taken together, our findings suggest that BET family proteins are involved in the suppression of TSLP production by 16D10. These proteins can contribute to the pathology of atopic dermatitis via TSLP regulation in keratinocytes and have potential as therapeutic targets in allergic diseases.",
keywords = "16D10, Allergy, Atopic dermatitis, BET family protein, Keratinocyte, Thymic stromal lymphopoietin",
author = "Ryosuke Segawa and Hiroyuki Takeda and Takeshi Yokoyama and Momoha Ishida and Chihiro Miyata and Taiji Saito and Ryosuke Ishihara and Tomoya Nakagita and Yusuke Sasano and Naoki Kanoh and Yoshiharu Iwabuchi and Mineyuki Mizuguchi and Masahiro Hiratsuka and Noriyasu Hirasawa",
note = "Funding Information: This work was funded in part Grant-in-aid of Challenging Exploratory Research (17 K19470) from the Japan Society for the Promotion of Science and the Translational Research Network Program from the Japan Agency for Medical Research and Development. The establishment and screening of the protein arrays used in this study were conducted with financial support from the Takeda Science Foundation and the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) . cDNA resources were provided in collaboration with the Kazusa DNA Research Institute. We gratefully acknowledge the synchrotron radiation facility at the PF, Japan. X-ray diffraction experiments at the Photon Factory were performed with the approval of the High Energy Accelerator Research Organization (Proposal No. 2019G016 ). Funding Information: This work was funded in part Grant-in-aid of Challenging Exploratory Research (17 K19470) from the Japan Society for the Promotion of Science and the Translational Research Network Program from the Japan Agency for Medical Research and Development. The establishment and screening of the protein arrays used in this study were conducted with financial support from the Takeda Science Foundation and the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT). cDNA resources were provided in collaboration with the Kazusa DNA Research Institute. We gratefully acknowledge the synchrotron radiation facility at the PF, Japan. X-ray diffraction experiments at the Photon Factory were performed with the approval of the High Energy Accelerator Research Organization (Proposal No. 2019G016). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = dec,
doi = "10.1016/j.bcp.2021.114819",
language = "English",
volume = "194",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
}
