Gees Maarten, Musch Sara, Van der Plas Steven, Wesse Anne-Sophie, Vandevelde Ann, Verdonck Katleen, Mammoliti Oscar, Hwang Tzyh-Chang, Sonck Kathleen, Stouten Pieter, Swensen Andrew M, Jans Mia, Van der Schueren Jan, Nelles Luc, Andrews Martin, Conrath Katja
Galapagos NV, Mechelen, Belgium.
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States.
Front Pharmacol. 2018 Oct 26;9:1221. doi: 10.3389/fphar.2018.01221. eCollection 2018.
There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients.
对于大多数囊性纤维化（CF）患者的治疗，仍存在未满足的高度需求。识别和开发新型囊性纤维化跨膜传导调节因子（CFTR）调节剂对于在患者中实现更高的临床获益是必要的。在本报告中，我们描述了新型增强剂的特性。通过对F508del CFTR进行小规模筛选，开发出了活性化合物，从而鉴定出临床前候选药物GLPG1837和GLPG2451，它们各自来源于不同的化学系列。这两种候选药物均可增强野生型CFTR的活性以及低温或校正剂挽救的F508del CFTR的活性，并且能够改善一系列III类、IV类CFTR突变体的通道活性。当使用跨上皮钳制电路（TECC）进行测量时，在YFP卤化物测定中观察到的活性很好地转化到了来源于CF肺部的原代细胞中。两种增强剂均以相似的方式改善F508del CFTR通道的开放，增加通道的开放时间并减少关闭时间。在对校正后的F508del CFTR进行长期评估时，未观察到增强剂存在时通道活性的降低。当前的工作鉴定并表征了新型CFTR增强剂GLPG1837和GLPG2451，它们可能为CF患者提供新的治疗选择。
