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

Biochemical Pharmacology
Young Hwan ParkWahn Soo Choi

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 (IC50, ∼27.9 nM) and BMMCs (IC50, ∼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 (IC50, ∼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 (ED50, ∼35.8 mg/kg). Altogether, these results suggest that AZD7762 could be used as a new therap...Continue Reading

Citations

Feb 6, 2020·British Journal of Pharmacology·Li-Na ZhangJia-Jie Chen
Jun 3, 2020·The Journal of Clinical Investigation·Melanie C DispenzaBruce S Bochner
Aug 21, 2019·Journal of Translational Medicine·Yi-Bo HouJia-Jie Chen
Aug 1, 2020·Frontiers in Pharmacology·Misun KimDooil Jeoung
Oct 22, 2020·International Journal of Molecular Sciences·Akash AhujaJae Youl Cho
Jan 5, 2021·Frontiers in Immunology·Melanie C DispenzaDonald W MacGlashan
Apr 21, 2020·International Immunopharmacology·Yi-Bo HouJia-Jie Chen
May 30, 2021·The Journal of Allergy and Clinical Immunology·Hyun-Young JangByung-Hyun Park

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