Background:

GSK-7975A is a potent and orally available CRAC channel inhibitor.

GSK-7975A reduces FcεRI-dependent Ca2+ influx and 3 μM GSK-7975A reduces the release of histamine, leukotriene C4, and cytokines (IL-5/-8/-13 and TNFα) by up to 50%[1]. GSK-7975A inhibits mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety species. GSK-7975A completely inhibits calcium influx through CRAC channels. This leads to inhibition of the release of mast cell mediators and T-cell cytokines from multiple human and rat preparations. Mast cells from guinea-pig and mouse preparations are not inhibited by GSK-7975A; however cytokine release is fully blocked from T-cells in a mouse preparation[2]. GSK-7975A inhibits toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). GSK-7975A also prevents activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells[3].

GSK-7975A inhibits local and systemic features of acute pancreatitis in TLCS-AP, CER-AP, FAEE-AP, in dose- and time-dependent manners. GSK-7975A significantly reduces increases in serum amylase, IL6, and pancreatic MPO levels; lung MPO is reduced significantly by low dose only. GSK-7975A markedly reduces pancreatic histopathology in TLCS-AP, CER-AP, and FAEE-AP[3].

[1]. Ashmole I, et al. CRACM/Orai ion channel expression and function in human lung mast cells. J Allergy Clin Immunol. 2012 Jun;129(6):1628-35.e2. [2]. Rice LV, et al. Characterization of selective Calcium-Release Activated Calcium channel blockers in mast cells and T-cells from human, rat, mouse and guinea-pig preparations. Eur J Pharmacol. 2013 Mar 15;704(1-3):49-57. [3]. Wen L, et al. Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models. Gastroenterology. 2015 Aug;149(2):481-92.e7.