Читать книгу Clinical Pancreatology for Practising Gastroenterologists and Surgeons - Группа авторов - Страница 151

Physiological calcium signaling plays a pivotal role in every aspect of cellular life, and is a key determinant of cell death [16]. Within pancreatic acinar cells, sustained global rises of cytosolic calcium occur in response to pancreatic toxins, overwhelming resident calcium homeostatic mechanisms [7]. The sustained rise in calcium results in a range of downstream phenomena: zymogen granule trypsinogen activation, vacuole formation, mitochondrial dysfunction, and initiation of cell death, which is predominantly necrosis, all contributing to the pathogenesis of AP [7,11,13,17]. Sustained elevation of cytosolic calcium relies on continued emptying of the endoplasmic reticulum (ER) calcium store and activation of store‐operated calcium entry (SOCE) via plasma membrane localized calcium‐release activated calcium (CRAC) channels, replenishing the ER store. ORAI1 is the principal CRAC channel in pancreatic acinar cells, opening of which is coordinated by ER membrane‐expressed stromal interaction molecules (STIM1 and STIM2) following decreases in calcium concentrations within the ER lumen [18–21].

In recent years, several human diseases have been linked to abnormal CRAC channel activity, including severe combined immunodeficiency disorders, allergy, inflammatory bowel disease, thrombosis, brain injury, breast cancer, and AP [22,23]. As a result, pharmaceutical company researchers have invested considerable time and effort into developing potent CRAC inhibitors [24–26]. Two such ORAI1 channel inhibitors, GSK‐7975A (containing a pyrazole core structure) and CM4620 (also known as CM‐128, with a pyrazine core structure) were developed independently by GlaxoSmithKline (GSK, Stevenage, UK) and CalciMedica (La Jolla, CA), respectively [18,27]. GSK‐7975A has been demonstrated to inhibit SOCE induced by thapsigargin in isolated murine pancreatic acinar cells with an IC₅₀ of approximately 3.4 μM, inhibiting endocytic vacuole formation and reducing necrosis induced by toxins that cause AP [19]. The Liverpool Pancreatitis Research Group conducted a thorough preclinical validation study evaluating the effect of GSK‐7975A and CalciMedica’s CM4620 in ex vivo and in vivo experimental AP using three clinically relevant models [26]. Both GSK‐7975A and CM4620 showed concentration‐dependent inhibitory effects on SOCE and necrosis in murine and human pancreatic acinar cells induced by taurolithocholic acid 3‐sulfate (TLCS) or cholecystokinin (CCK)‐8. The effects of CM4620 on ORAI1 were substantiated by examination of its effect on CRAC currents in ORAI1/STIM1‐transfected HEK 293 cells. The in vitro work informed in vivo pharmacokinetic analysis. GSK‐7975A was given at selected doses after induction of AP with TLCS (TLCS‐AP) or seven injections of cerulein (CER‐AP) or ethanol and palmitoleic acid (FAEE‐AP) [26,28]. Because GSK‐7975A markedly reduced all pathological parameters in a dose‐dependent manner, a high dose of GSK‐7975A and separately CM4620 was begun at two different time points after disease induction, to determine the effect of early versus late drug administration. Drug administration that was begun one hour after disease induction was highly effective in reducing all pathological parameters, and significantly more effectively than drug administration begun six hours after disease induction, in all models.

On the basis of these strong preclinical data, an intravenous formulation of CM4620 went through preclinical toxicity assessment into clinical development. Following a successful Phase I study in early 2017 (NCT03709342), the drug was fast‐tracked in early 2018 by the US Food and Drug Administration (FDA) and was taken into a Phase IIA trial (NCT03401190) for predicted moderate to severe pancreatitis. The results remain eagerly awaited as inhibition of calcium toxicity is a strategy that may prove successful in the treatment of AP.