Biomolecules & Therapeutics  
An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
Young Hwan Park1,†, Hyun Woo Kim1,†, Hyuk Soon Kim1, Seung Taek Nam1, Dajeong Lee1, Min Bum Lee1, Keun Young Min1, Jimo Koo1, Su Jeong Kim1, Young Mi Kim2, Hyung Sik Kim3 and Wahn Soo Choi1,*
1Department of Immunology, College of Medicine, Konkuk University, Chungju 27478,
2College of Pharmacy, Duksung Women’s University, Seoul 01369,
3Division of Toxicology, College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
E-mail: wahnchoi@kku.ac.kr
Tel: +82-2-2030-7813, Fax: +82-2-2030-7845
The first two authors contributed equally to this work.
Received: August 1, 2018; Revised: August 20, 2018; Accepted: August 21, 2018; Published online: October 11, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

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 (IC50, ~1.42 μM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC50, ~1.10 μM), and IL-6 (IC50, ~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.
Keywords: CYC116, Mast cells, Allergy, Immunoglobulin (Ig) E, Fyn, Syk


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