Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Sci Rep. 2017 Oct 16;7(1):12881. doi: 10.1038/s41598-017-13343-x.
The store-operated calcium entry (SOCE) pathway is an important route for generating cytosolic Ca signals that regulate a diverse array of biological processes. Abnormal SOCE seem to underlie several diseases that notably include allergy, inflammation and cancer. Therefore, any modulator of this pathway is likely to have significant impact in cell biology under both normal and abnormal conditions. In this study, we screened the FDA-approved drug library for agents that share significant similarity in 3D shape and surface electrostatics with few, hitherto best known inhibitors of SOCE. This has led to the identification of five drugs that showed dose-dependent inhibition of SOCE in cell-based assay, probably through interacting with the Orai1 protein which effectively mediates SOCE. Of these drugs, leflunomide and teriflunomide could suppress SOCE significantly at clinically-relevant doses and this provides for an additional mechanism towards the therapeutic utility of these drugs as immunosuppressants. The other three drugs namely lansoprazole, tolvaptan and roflumilast, were less potent in suppressing SOCE but were more selective and thus they may serve as novel scaffolds for future development of new, more efficacious SOCE inhibitors.
钙库操纵性钙内流（SOCE）途径是产生细胞溶质 Ca 信号的重要途径，调节着广泛的生物过程。异常的 SOCE 似乎是几种疾病的基础，这些疾病包括过敏、炎症和癌症。因此，该途径的任何调节剂在正常和异常条件下都可能对细胞生物学产生重大影响。在这项研究中，我们筛选了 FDA 批准的药物库，寻找与 SOCE 少数先前已知的抑制剂在 3D 形状和表面静电方面具有显著相似性的药物。这导致鉴定了五种药物，它们在基于细胞的测定中显示出剂量依赖性的 SOCE 抑制作用，可能通过与有效地介导 SOCE 的 Orai1 蛋白相互作用来实现。在这些药物中，来氟米特和特立氟胺在临床相关剂量下可显著抑制 SOCE，这为这些药物作为免疫抑制剂的治疗用途提供了另一种机制。其他三种药物，即兰索拉唑、托伐普坦和罗氟司特，抑制 SOCE 的作用较弱，但选择性更强，因此它们可能成为未来开发更有效 SOCE 抑制剂的新型支架。
