copied from "Clinical Relevance of Target Identity and Biology: Implications for Drug Discovery and Development" J Biomol Screen 2013 18: 1164
Recent advances in the treatment of cystic fibrosis provide an example of how personalized medicine can occur with- out knowing the precise target of a novel therapeutic and can be applied with limited provider understanding of the biology at work. Cystic fibrosis is a fatal genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a mul- tifunctional protein whose primary role is as an adenosine triphosphate (ATP)–gated chloride channel essential for normal salt and fluid transport in multiple organs, including the lung.102 The discovery of the CFTR gene in 1989 prompted the development of therapeutic approaches to restore normal CFTR function, either through replacement of CFTR through gene therapy or by improving the function of the mutant CFTR.103 The latter is complicated by the fact that different mutations predictably affect the CFTR protein and its function in different ways.102,104,105 While the most common CFTR mutation, ΔF508, results in both impaired trafficking to the cell surface and problems with channel gating, other less common mutations, such as G551D, affect only channel gating.104–106
Using cells expressing mutant CFTR genes, Van Goor and colleagues106 at Vertex Pharmaceuticals screened 228,000 compounds for compounds that would enhance CFTR function using a cell-based fluorescence membrane potential assay. Specifically, they screened for two types of compounds: CFTR correctors, which improve ΔF508 CFTR trafficking, and CFTR potentiators, which improve ΔF508 CFTR gating at the cell surface. From the CFTR potentiator screen, hit selection and lead optimization yielded ivacaftor (VX-770).