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Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2018 Aug; Vol. 154, pp. 270-277. Date of Electronic Publication: 2018 May 17. - Publication Year :
- 2018
-
Abstract
- Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC <subscript>50</subscript> , ∼27.9 nM) and BMMCs (IC <subscript>50</subscript> , ∼99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activated T cells (LAT), phospholipase (PL) Cγ1, Akt, and mitogen-activated protein (MAP) kinases (Erk1/2, p38, and JNK) in mast cells. In in vitro protein kinase assay, AZD7762 inhibited the activity of Lyn and Fyn kinases, which are important for the activation of Syk in mast cells. Furthermore, AZD7762 also suppressed the degranulation of LAD2 human mast cells (IC <subscript>50</subscript> , ∼49.9 nM) and activation of Syk in a dose-dependent manner. As observed in experiments with mast cells in vitro, AZD7762 inhibited antigen-mediated passive cutaneous anaphylaxis in mice (ED <subscript>50</subscript> , ∼35.8 mg/kg). Altogether, these results suggest that AZD7762 could be used as a new therapeutic agent for mast cell-mediated allergic diseases.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Degranulation drug effects
Cell Degranulation physiology
Cells, Cultured
Dose-Response Relationship, Drug
Drug Repositioning methods
Humans
Immunoglobulin E toxicity
Male
Mast Cells immunology
Mast Cells metabolism
Mice
Mice, Inbred BALB C
Proto-Oncogene Proteins c-fyn metabolism
Rats
Urea pharmacology
src-Family Kinases metabolism
Anti-Allergic Agents pharmacology
Antineoplastic Agents pharmacology
Mast Cells drug effects
Proto-Oncogene Proteins c-fyn antagonists & inhibitors
Thiophenes pharmacology
Urea analogs & derivatives
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 154
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 29777684
- Full Text :
- https://doi.org/10.1016/j.bcp.2018.05.012