AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d]Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response

Abstract

Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC 50 , approx. 0.58 μM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC 50 , approx. 0.09 μM) and TNF-α (IC 50 , approx. 0.19 μM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

Drug repositioning of anti-microbial agent nifuratel to treat mast cell-mediated allergic responses

“…35 Our research focused on exploring the potential of various compounds for drug repositioning in the treatment of mast cell-dependent allergic diseases. [36][37][38] 5-Nitrofuran has been used in clinical settings for over 60 years. The furan ring system is a widely utilized skeleton for various compounds and has been observed to impart biological activities, including antibacterial, anti-inflammatory, and antifungal effects.…”

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

“…Several structurally similar compounds were developed based on tozasertib model, such as ENMD-2076, an orally active potent inhibitor of AurA and of other cancer-related kinases [ 66 , 67 ], and AT9283, a 4-pyrazolamine derivative with broad-spectrum activity against a variety of kinases [ 68 , 69 ].…”