The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway

Graeme W. Carlile*, Qi Yang, Elizabeth Matthes, Jie Liao, Véronique Birault, Helen F. Sneddon, Darren L. Poole, Callum J. Hall, John W. Hanrahan, David Y. Thomas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.

Original languageEnglish
Article number4595
Number of pages19
JournalScientific reports
Issue number1
Publication statusPublished - 17 Mar 2022

Bibliographical note

Funding Information:
The work was supported by grants from the Canadian Institutes of Health Research to D.Y. T (MOP-119341), JH (MOP-287879), and J.W.H. and D.Y.T. (PJT-156183), Cystic Fibrosis Canada (#561848) and by funding from Cystic Fib Canada for the Primary Airway Cell Biobank at the McGill CF Translational Research Center (CFTRc).

Publisher Copyright:
© 2022, The Author(s).

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