CFTR potentiators and correctors and bifunctional (corrector/potentiator) compounds for treatment of Cystic Fibrosis

Full Description

UCSF investigators have isolated set of compounds  to treat cystic fibrosis (CF). The compounds are anticipated to treat the underlying defects in patients with the delta F508 mutation of the CFTR gene, which is present in around 90% of the CF cases. Small molecule therapy directed toward correcting the deltaF508 defects in cellular processing and channel gating of CFTR is thought to hold considerable promise.

A panel of novel potentiators (which restore gating defects) and correctors (which restore protein folding and plasma membrane trafficking) are available for licensing. Several of the potentiators identified are very potent (some at submicromolar potency) in restoring the gating defect in both deltaF508 mutants and other CFTR gating mutants, including G551D. They have also identified several highly effective (micromolar potency) correctors of the deltaF508 mutant protein. When used in combination, these compounds may correct the defects caused by the deltaF508 mutation in the CFTR gene.

Publications

• Yang et al. (2003) The Journal of Biological Chemistry. Nanomolar affinity small molecule correctors of defective deltaF508-CFTR chloride channel gating.
  
• Pedemonte et al. (2006) Molecular Pharmacology. Phenylglycine and Sulfonamide correctors of defective deltaF508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating.
• Pedemonte et al. (2005) Journal of Clinical Investigation. Small-molecule correctors of defective deltaF508-CFTR cellular processing identified by high-throughput screening.
• Suen et al. (2006) Bioorganic and Medicinal Chemistry Letters. Sulfamoyl-4-oxoquinoline-3-carbamides:Novel potentiators of defective deltaF508-CFTR chloride channel gating.
• Yoo et al. (2008) Bioorganic and Medicinal Chemistry Letters. 4’-Methyl-4,5’-bithiazole-based correctors of deltaF508-CFTR cellular processing.
• Yu et al. (2008) Journal of Medicinal Chemistry. Potent s-cis-Locked   Bithiazole correctors of deltaF508 CFTR cellular processing for cystic fibrosis therapy.
• Ye et al. Pyrazolylthiazole as DeltaF508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles. J Med Chem. 2010 May 13;53(9):3772-81.
  

Related Materials

• 1. Yang et al. (2003) The Journal of Biological Chemistry. Nanomolar affinity small molecule correctors of defective deltaF508-CFTR chloride channel gating.
• 2. Pedemonte et al. (2006) Molecular Pharmacology. Phenylglycine and Sulfonamide correctors of defective deltaF508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating.
• 3. Pedemonte et al. (2005) Journal of Clinical Investigation. Small-molecule correctors of defective deltaF508-CFTR cellular processing identified by high-throughput screening.
• 4. Suen et al. (2006) Bioorganic and Medicinal Chemistry Letters. Sulfamoyl-4-oxoquinoline-3-carbamides:Novel potentiators of defective deltaF508-CFTR chloride channel gating.
• 5. Yoo et al. (2008) Bioorganic and Medicinal Chemistry Letters. 4’-Methyl-4,5’-bithiazole-based correctors of deltaF508-CFTR cellular processing.
• 6. Yu et al. (2008) Journal of Medicinal Chemistry. Potent s-cis-Locked Bithiazole correctors of deltaF508 CFTR cellular processing for cystic fibrosis therapy.
• 7. Ye et al. (2010) Pyrazolylthiazole as DeltaF508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles.

Patent Information

UCSF has a large portfolio of both US and foreign patent applications covering the use of these compounds for treatment of CF. Below are some selected patent application publications

Patent Status