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Molecular Pharmacology Fast Forward
First published on November 1, 2007; DOI: 10.1124/mol.107.040725

0026-895X/08/7302-478-489$20.00
Mol Pharmacol 73:478-489, 2008

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Structural Analog of Sildenafil Identified as a Novel Corrector of the F508del-CFTR Trafficking Defect

Renaud Robert, Graeme W. Carlile, Catalin Pavel, Na Liu, Suzana M. Anjos, Jie Liao, Yishan Luo, Donglei Zhang, David Y. Thomas, and John W. Hanrahan

Departments of Physiology (R.R., C.T., N.L., J.L., Y.L., J.W.H.) and Biochemistry (G.W.C., S.M.A., D.Z., D.Y.T.), McGill University, Montréal, Québec, Canada

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.

Received for publication August 8, 2007.

Accepted for publication November 1, 2007.

Address correspondence to: Dr. Renaud Robert, McIntyre Building, Physiology Department, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada. E-mail: renaud.robert{at}mcgill.ca




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