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Pulmonary disease

Cystic fibrosis (CF)

Cystic fibrosis transmembrane conductance regulator (CFTR)

In vitro and cell culture studies identified the molecular mechanism of action for CFTR corrector compounds and suggest new combination approaches that could help treat CF. In reconstituted phospholipid bilayers carrying recombinant ΔF508 CFTR, the corrector compound VX-809 directly bound the protein and stabilized the interface between nucleotide binding domain 1 and membrane spanning domains 1 and 2. In cultured cells and samples from patients with CF that have the ΔF508 CFTR mutation, VX-809 plus either of two compounds that help stabilize protein folding increased functional CFTR expression compared with any individual treatment. Next steps include identifying drug-like stabilizers of NBD1 folding, which could be combined with VX-809 or other CFTR correctors.
Vertex Pharmaceuticals Inc.'s VX-809, a CFTR corrector, is in Phase III trials to treat ΔF508 mutant CF in combination with the CFTR potentiator Kalydeco ivacaftor (VX-770).
Vertex's VX-661, a CFTR corrector that is structurally related to VX-809, is in Phase II trials in combination with Kalydeco to treat ΔF508 CF.
Vertex markets Kalydeco to treat CF.

SciBX 6(22); doi:10.1038/scibx.2013.553
Published online June 6, 2013

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Okiyoneda, T. et al. Nat. Chem. Biol.; published online May 12, 2013;
Contact: Gergely L. Lukacs, McGill University, Montreal, Quebec, Canada