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

doi:10.1016/j.bcp.2021.114819

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

Biochem Pharmacol. 2021 Dec:194:114819. doi: 10.1016/j.bcp.2021.114819. Epub 2021 Oct 30.

Affiliations

¹ Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai Miyagi 980-8578, Japan.
² Proteo-Science Center, Ehime University, Ehime 790-8577, Japan.
³ Laboratiry of Structural Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
⁴ Laboratory of Synthetic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
⁵ Laboratory of Organic and Biomolecular Chemistry, School of Pharmacy and Pharmaceutical Sciences, and Institute of Medical Chemistry, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
⁶ Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai Miyagi 980-8578, Japan. Electronic address: noriyasu.hirasawa.c7@tohoku.ac.jp.

PMID: 34757034
DOI: 10.1016/j.bcp.2021.114819

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Chalcones / chemistry
Chalcones / metabolism*
Chalcones / pharmacology*
Crystallography, X-Ray
Cytokines / antagonists & inhibitors*
Cytokines / biosynthesis
Dose-Response Relationship, Drug
Humans
Keratinocytes / drug effects*
Keratinocytes / metabolism*
Mice
Mice, Inbred BALB C
Nerve Tissue Proteins / metabolism*
Protein Binding / physiology
Protein Structure, Secondary
Receptors, Cell Surface / metabolism*
Thymic Stromal Lymphopoietin

Substances

Chalcones
Cytokines
Dner protein, mouse
Nerve Tissue Proteins
Receptors, Cell Surface
Thymic Stromal Lymphopoietin