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, John W. Hanrahan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)478-489
Number of pages12
JournalMolecular Pharmacology
Issue number2
StatePublished - Feb 1 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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