Store-Operated Calcium Entry Inhibitors: Structural Diversity, Mechanisms of Action, and Optimization Strategies

Store-operated calcium entry (SOCE) is a ubiquitous calcium influx pathway critically involved in numerous physiological processes. Dysregulated SOCE contributes to the pathogenesis of cardiovascular disorders, cancer, and neurodegenerative diseases, making SOCE modulators promising therapeutic candidates. This review provides an overview of the major chemical classes of classical SOCE inhibitors that target Orai and STIM proteins. We focus on structure–activity relationships (SARs), mechanisms of action, strategies for enhancing inhibitory potency and selectivity, and discuss the limitations and side-effect profiles of these compounds. This comprehensive analysis identifies SOC channels as promising therapeutic targets and outlines future directions for rational drug design and the development of clinically viable SOCE modulators.