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
  • 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. [email protected].
  • 2. Department of Human Genetics, Cystic Fibrosis Translational Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada. [email protected].
  • 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.

Products