Biomol Ther.  2019 May;27(3):311-317. 10.4062/biomolther.2018.148.

An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells

• Park YH
• Kim HW
• Kim HS
• Nam ST
• Lee D
• Lee MB
• Min KY
• Koo J
• Kim SJ
• Kim YM
• Kim HS
• Choi WS

• KMID: 2447858
• DOI: http://doi.org/10.4062/biomolther.2018.148

Abstract

Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation (ICâ‚…â‚€, ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (ICâ‚…â‚€, ∼1.10 µM), and IL-6 (ICâ‚…â‚€, ∼1.24 µM). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ∼22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, PLCγ, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.

Keyword

CYC116; Mast cells; Allergy; Immunoglobulin (Ig) E; Fyn; Syk

MeSH Terms

Anaphylaxis
Animals
Cytokines
Dermatitis, Atopic
Hypersensitivity
Interleukin-6
Mast Cells*
Mice
Passive Cutaneous Anaphylaxis
Phosphotransferases*
Rhinitis, Allergic
Cytokines
Interleukin-6
Phosphotransferases