A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins

Ryosuke Segawa, Hiroyuki Takeda, Takeshi Yokoyama, Momoha Ishida, Chihiro Miyata, Taiji Saito, Ryosuke Ishihara, Tomoya Nakagita, Yusuke Sasano, Naoki Kanoh, Yoshiharu Iwabuchi, Mineyuki Mizuguchi, Masahiro Hiratsuka, Noriyasu Hirasawa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number114819
JournalBiochemical Pharmacology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • 16D10
  • Allergy
  • Atopic dermatitis
  • BET family protein
  • Keratinocyte
  • Thymic stromal lymphopoietin

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