Cystic Fibrosis (CF) is the most common life-threatening autosomal recessive disease affecting approximately 75,000 patients worldwide, predominantly of Caucasian origin. CF is caused by decreased chloride transport across epithelial tissues due to defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) proteins which result from mutations in the CFTR gene. Currently, over 1900 CFTR mutations are known. Approximately 70%1 of CF patients have a mutation that causes the deletion of phenylalanine at position 508 (F508del-CFTR) and results in improper folding of the protein, decreasing both channel surface density and gating. Another 4-5% of CF patients present the missense G551D mutation where the amino acid aspartic acid (D) is added instead of a glycine (G) leading to impaired gating of the protein present at the cell surface. Using high throughput screening (HTS) pharmacological agents that modulate CFTR protein activity leading to enhanced chloride transport were identified. This presentation will describe the approach and the subsequent medicinal chemistry efforts that culminated with the discovery of novel CFTR modulators. 1http://cftr2.org/files/CFTR2_13August2015.pdf

Discovery of CFTR modulators for the treatment of cystic fibrosis

251st National Meeting (2016)

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