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

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

  • Sci Rep. 2022 Mar 17;12(1):4595. doi: 10.1038/s41598-022-08661-8.
Graeme W Carlile 1 2,  Qi Yang 3 4,  Elizabeth Matthes 5,  Jie Liao 5,  Véronique Birault 6,  Helen F Sneddon 7,  Darren L Poole 8,  Callum J Hall 8,  John W Hanrahan 5,  David Y Thomas 3 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, Cystic Fibrosis Translational Research Centre, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. graeme.carlile@mcgill.ca.
  • 2 Department of Human Genetics, Cystic Fibrosis Translational Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada. graeme.carlile@mcgill.ca.
  • 3 Department of Biochemistry, Cystic Fibrosis Translational Research Centre, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
  • 4 Department of Human Genetics, Cystic Fibrosis Translational Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada.
  • 5 Department of Physiology, McGill Cystic Fibrosis Translational Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada.
  • 6 Translation Department, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 7 Department of Chemistry, Green Chemistry Centre of Excellence, University of York, Heslington, York, YO10 5DD, UK.
  • 8 Medicinal Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
PMID: 35302062 DOI: 10.1038/s41598-022-08661-8
Abstract

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.

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