It should be noted that while several rounds of analogue synthesis and testing were required to go from the hit VRT-532 to drug VX-770, compounds were strictly assessed for an effect on ion transport in mutant CFTR- expressing cells, rather than CFTR binding or other assays of isolated CFTR protein. While ivacaftor is unable to restore normal CFTR function to cells with the ΔF508 mutant CFTR, due to its dual defects in trafficking and gat- ing, it restores normal CFTR function in cells with G551D, as this mutation only affects gating.107 For this reason, iva- caftor was moved into clinical trials for the treatment of patients with cystic fibrosis with the G551D mutation and found to improve not only sweat chloride measurements, reflecting the improvement in CFTR function, but also lung function and nutritional status, both important clinical parameters, leading to its approval for the treatment of patients 6 years and older with this mutation in January 2012.103
This would represent a triumph for target-based drug discovery had ivacaftor been developed with the CFTR as a target, based on structural studies of the CFTR protein— developing a precise molecular mechanism of action to repair the defects in the mutant channel. Instead, ivacaftor represents the development of a genotype-specific person- alized therapeutic using phenotypic drug discovery meth- ods and, as such, provides a counterexample to the widely held assertion that personalized medicine is only possible using the target-based drug discovery approach. Indeed, the exact mechanism by which ivacaftor exerts its beneficial effects on CFTR gating is still unclear, and although recent work suggests direct action on CFTR itself,108 this was not by design. Phenotypic drug discovery can yield targeted, personalized therapeutics.