Lumacaftor ( VX -809) is a pharmaceutical drug that acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It is available in a single pill with ivacaftor; the combination, lumacaftor/ivacaftor (brand name Orkambi), is used to treat people with cystic fibrosis who are homozygous for the F508del mutation in the cystic fibrosis …
Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for the optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. … Binding to VX -809 leads to a significant negative shift in NBD1 thermal melting temperature …
VX -809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX -809 action .
6/11/2015 · VX?809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX?809 increases the stability of F508del?CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue. … However, the mechanism of action (MoA) of these compounds/drugs is still not …
7/25/2013 · VX -809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX -809 is additive or synergistic with genetic revertants of F508del-CFTR, other.
The mechanism of action of VX -809 remains largely unknown. Given that VX -809 does not stabilize isolated NBD1 (Loo et al.
2013), it has been suggested to act by correcting domain-domain interface …
VX -809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX -809 is additive or …
VX -809 exerted an allosteric effect on MSD2, supporting a new hypothesis wherein the two compounds exert an interacting mechanism of action . The interacting effect of the two compounds was revealed in studies of full-length F508del-CFTR bearing MSD:NBD1 interface mutants.
Lumacaftor is an aromatic amide obtained by formal condensation of the carboxy group of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid with the aromatic amino group of 3-(6-amino-3-methylpyridin-2-yl)benzoic acid.Used for the treatment of cystic fibrosis. It has a role as a CFTR potentiator and an orphan drug.
The ASL screens also yielded robust correctors that combined strongly with the clinical corrector VX -809, consistent with modes of action distinct from VX -809. Different mechanisms of action could include binding to different sites on CFTR or interaction with different proteins that modulate CFTR expression, folding, trafficking, or degradation.
