The creation of future drugs derived from the nonsteroidal anti-inflammatory drug (NSAID) glafenine may help patients with cystic fibrosis (CF) with certain mutations, according to a new study published in Scientific Reports.
The compounds tested during the study were found to correct the trafficking of the most common CF-causing mutation of the cystic fibrosis transmembrane regulator (CFTR), F508del-CFTR. Studies show that the F508del-CFTR is the most common class 2 mutant and occurs in approximately 90% of patients with CF.
A glafenine derivative and a prostaglandin E synthase 1,2,3 (PGES 1,2,3) inhibitor were also found to correct other class 2 mutations including the rarer N1303K and G85E mutants. Both compounds were found to be more effective than elexacaftor/tezacaftor/ivacaftor at correcting G85E mutations in a cellular model.
A total of 38 NSAIDs were tested and it was found that 7 out of 8 NSAID classes contained compounds that provided a significant correction to the levels of F508del-CFTR trafficked to the cell surface. Of the NSAIDs tested, glafenine was the most effective with the restoration of 27.5% of wild-type surface CFTR levels.
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Medicinal chemistry was utilized to develop 55 analogs of glafenine to find a more effective version. One derivative, compound 49, was able to achieve a 4-fold increase in F508del-CFTR correction compared to glafenine in human primary bronchial epithelial cells (HBE).
Further analysis found that glafenine targets cyclooxygenase 2 and works via the arachidonic acid pathway. Glafenine’s mechanism of action was found to be through the prevention of arachidonic acid conversion to prostaglandin E2. The PGES 1,2,3 inhibitor 2-(9-chloro-1H-phenanthro [9,10-d] imidazol-2-yl)-1,3-benzenedicarbonitrile (MF63) was also found to be a potent proteostatic regulator of F508del-CFTR.
“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,” the authors said.
Both compound 49 and MF63 were found to give a higher surface expression of CFTR than elexacaftor/tezacaftor/ivacaftor in HBE cells from a patient who was heterozygous for G85E and a class 1 mutation (621+1GT) that does not produce a full-length CFTR. Elexacaftor/tezacaftor/ivacaftor produced 6.1% of wild-type expression while compound 49 and MF63 produced 9.5% and 13.4%, respectively.
Carlile GW, Yang Q, Matthes E, et al. The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway. Sci Rep. 2022;12(1):4595. doi:10.1038/s41598-022-08661-8