Targeting the Orai1 CRAC channel: translating molecular insights into therapeutic progress

The Ca²⁺ release-activated Ca²⁺ (CRAC) channel, triggered by the interaction between the Ca²⁺ sensor STIM1 and Orai1, is the primary mediator of store-operated calcium entry (SOCE). Dysregulation of this process drives numerous human pathologies, particularly immune disorders and cancer hallmarks. Due to its role, Orai1 has emerged as an attractive target for precision therapeutics.

This review outlines the pharmacological evolution of CRAC channel modulators, tracing their development from early chemical tools, such as SKF-96365, that exhibits several off-target effects, to more selective second-generation pore blockers, including Synta66, RO2959 or GSK-7975A. Particular attention is paid to third-generation inhibitors, especially CM4620 (zegocractin), evaluating data from recent Phase 2 clinical trials in acute pancreatitis (CARPO), severe COVID-19 pneumonia (CARDEA), and acute kidney injury (KOURAGE). We describe emerging orally bioavailable candidates like CM5480 aimed at chronic cardiopulmonary remodeling.

Clinical experience reveals that targeting ubiquitous Ca²⁺ pathways, such as SOCE, demands specific trial design, transitioning toward biomarker-driven stratification of patient cohorts. Over the coming years, the pharmacological design will diverge into acute intravenous critical care and chronic oral immunomodulation. Ultimately, the exploitation of tissue-specific Orai2 and Orai3 isoform profiles represents the next frontier to enhance therapeutic efficacy across distinct disorders.