Cargando…

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

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 o...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Young Hwan, Kim, Hyun Woo, Kim, Hyuk Soon, Nam, Seung Taek, Lee, Dajeong, Lee, Min Bum, Min, Keun Young, Koo, Jimo, Kim, Su Jeong, Kim, Young Mi, Kim, Hyung Sik, Choi, Wahn Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Society of Applied Pharmacology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513188/
https://www.ncbi.nlm.nih.gov/pubmed/30332888
http://dx.doi.org/10.4062/biomolther.2018.148
_version_ 1783417734423379968
author Park, Young Hwan
Kim, Hyun Woo
Kim, Hyuk Soon
Nam, Seung Taek
Lee, Dajeong
Lee, Min Bum
Min, Keun Young
Koo, Jimo
Kim, Su Jeong
Kim, Young Mi
Kim, Hyung Sik
Choi, Wahn Soo
author_facet Park, Young Hwan
Kim, Hyun Woo
Kim, Hyuk Soon
Nam, Seung Taek
Lee, Dajeong
Lee, Min Bum
Min, Keun Young
Koo, Jimo
Kim, Su Jeong
Kim, Young Mi
Kim, Hyung Sik
Choi, Wahn Soo
author_sort Park, Young Hwan
collection PubMed
description 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 (IC(50), ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC(50), ∼1.10 µM), and IL-6 (IC(50), ∼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.
format Online
Article
Text
id pubmed-6513188
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher The Korean Society of Applied Pharmacology
record_format MEDLINE/PubMed
spelling pubmed-65131882019-05-21 An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells Park, Young Hwan Kim, Hyun Woo Kim, Hyuk Soon Nam, Seung Taek Lee, Dajeong Lee, Min Bum Min, Keun Young Koo, Jimo Kim, Su Jeong Kim, Young Mi Kim, Hyung Sik Choi, Wahn Soo Biomol Ther (Seoul) Original Article 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 (IC(50), ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC(50), ∼1.10 µM), and IL-6 (IC(50), ∼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. The Korean Society of Applied Pharmacology 2019-05 2018-10-11 /pmc/articles/PMC6513188/ /pubmed/30332888 http://dx.doi.org/10.4062/biomolther.2018.148 Text en Copyright ©2019, The Korean Society of Applied Pharmacology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Park, Young Hwan
Kim, Hyun Woo
Kim, Hyuk Soon
Nam, Seung Taek
Lee, Dajeong
Lee, Min Bum
Min, Keun Young
Koo, Jimo
Kim, Su Jeong
Kim, Young Mi
Kim, Hyung Sik
Choi, Wahn Soo
An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title_full An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title_fullStr An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title_full_unstemmed An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title_short An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells
title_sort anti-cancer drug candidate cyc116 suppresses type i hypersensitive immune responses through the inhibition of fyn kinase in mast cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513188/
https://www.ncbi.nlm.nih.gov/pubmed/30332888
http://dx.doi.org/10.4062/biomolther.2018.148
work_keys_str_mv AT parkyounghwan ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyunwoo ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyuksoon ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT namseungtaek ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT leedajeong ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT leeminbum ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT minkeunyoung ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT koojimo ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimsujeong ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimyoungmi ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyungsik ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT choiwahnsoo ananticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT parkyounghwan anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyunwoo anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyuksoon anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT namseungtaek anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT leedajeong anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT leeminbum anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT minkeunyoung anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT koojimo anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimsujeong anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimyoungmi anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT kimhyungsik anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells
AT choiwahnsoo anticancerdrugcandidatecyc116suppressestypeihypersensitiveimmuneresponsesthroughtheinhibitionoffynkinaseinmastcells