PT  - JOURNAL ARTICLE
AU  - Renaud Robert
AU  - Graeme W. Carlile
AU  - Catalin Pavel
AU  - Na Liu
AU  - Suzana M. Anjos
AU  - Jie Liao
AU  - Yishan Luo
AU  - Donglei Zhang
AU  - David Y. Thomas
AU  - John W. Hanrahan
TI  - Structural Analog of Sildenafil Identified as a Novel Corrector of the F508del-CFTR Trafficking Defect
AID  - 10.1124/mol.107.040725
DP  - 2008 Feb 01
TA  - Molecular Pharmacology
PG  - 478--489
VI  - 73
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/73/2/478.short
4100  - http://molpharm.aspetjournals.org/content/73/2/478.full
SO  - Mol Pharmacol2008 Feb 01; 73
AB  - The F508del mutation impairs trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) to the plasma membrane and results in a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We recently used a novel high-throughput screening (HTS) assay to identify small-molecule correctors of F508del CFTR trafficking and found several classes of hits in a screen of 2000 compounds (Carlile et al., 2007). In the present study, we have extended the screen to 42,000 compounds and confirmed sildenafil as a corrector using this assay. We evaluated structural analogs of sildenafil and found that one such molecule called KM11060 (7-chloro-4-{4-[(4-chlorophenyl) sulfonyl] piperazino}quinoline) was surprisingly potent. It partially restored F508del trafficking and increased maturation significantly when baby hamster kidney (BHK) cells were treated with 10 nM for 24 h or 10 μM for 2 h. Partial correction was confirmed by the appearance of mature CFTR in Western blots and by using halide flux, patch-clamp, and short-circuit current measurements in unpolarized BHK cells, monolayers of human airway epithelial cells (CFBE41o-), and intestines isolated from F508del-CFTR mice (Cftrtm1Eur) treated ex vivo. Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics. The American Society for Pharmacology and Experimental Therapeutics