Orai channels are pore forming proteins which underlie calcium release-activated calcium (CRAC) channels. In numerous cell types, calcium influx is predominantly governed by store-operated calcium channels (SOCs). The process of store-operated calcium entry (SOCE) is orchestrated through the concerted interaction of two essential molecular components: the pore-forming Orai proteins (Orai1-3) and the endoplasmic reticulum calcium-sensing stromal interaction molecules (STIM1 and STIM2) [4].

The pathophysiological effect of functional CRAC channel deficiency can be caused by loss-of-function mutations in ORAI1 or STIM molecules. Such CRAC channelopathies are characterised by impaired immune cell function and have been identified as an underlying cause of primary immunodeficiency with predominant features that resemble severe combined immunodeficiency disease.
ORAI1 and ORAI2 proteins form heteromeric complexes that constitute the pore of Ca²⁺ release-activated Ca²⁺ (CRAC) channels. Mice with double Orai1/Orai2 knockout have severely impaired T cell function.
NCT04195347 is a phase I/II trial evaluating CM4620 (Auxora™), a CRAC channel inhibitor, for treating asparaginase-associated pancreatitis in pediatric and young adult leukemia/lymphoma patients. The study focuses on determining CM4620's safety, tolerability, and optimal dosing, while exploring its ability to prevent severe complications such as pancreatic necrosis, pseudocyst formation, and SIRS. Administered intravenously over four days soon after symptom onset, CM4620 is being tested as a targeted approach to limit calcium overload-driven pancreatic injury and inflammation, with results expected after 2026 [2].

* Key recommended reading is highlighted with an asterisk

* Lewis RS. (2020) Store-Operated Calcium Channels: From Function to Structure and Back Again. Cold Spring Harb Perspect Biol, 12 (5). DOI: 10.1101/cshperspect.a035055 [PMID:31570335]

* Rubaiy HN. (2023) ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets. Pharmaceuticals (Basel), 16 (2). [PMID:37259313]

1. Bartoli F, Bailey MA, Rode B, Mateo P, Antigny F, Bedouet K, Gerbaud P, Gosain R, Plante J, Norman K et al.. (2020) Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca²⁺ Handling After Pressure Overload. Circulation, 141 (3): 199-216. [PMID:31906693]

2. Bruen C, Miller J, Wilburn J, Mackey C, Bollen TL, Stauderman K, Hebbar S. (2021) Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome: Clinical Development of a Calcium Release-Activated Calcium Channel Inhibitor. Pancreas, 50 (4): 537-543. [PMID:33939666]

3. Liardo E, Pham AT, Ghilardi AF, Zhelay T, Szteyn K, Gandi NL, Ekkati A, Koerner S, Kozak JA, Sun L. (2024) Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold. Eur J Med Chem, 278: 116805. [PMID:39232360]

4. Rubaiy HN. (2023) ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets. Pharmaceuticals (Basel), 16 (2). [PMID:37259313]

5. Velicelebi G, Stauderman K, Dunn M, Roos J. (2016) Pancreatitis treatment. Patent number: WO2016138472A1. Assignee: Calcimedica, Inc.. Priority date: 27/02/2015. Publication date: 01/09/2016.