[2016 SLAS Conference Poster] Phenotypic Characterization of CFTR Drugs, VX-770 and VX-809, in BioMAP®
Human Primary Cell Systems Connects Target Biology to Disease Mechanisms
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- 2016 SLAS Conference Poster
Cystic fibrosis (CF) patients have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that result in reduced membrane expression and function. CF patients have impaired lung function due to chronic airway inflammation driven by dysregulated Th17 and Th2 immune responses. These responses lead to overproduction of mucous and increased susceptibility to Pseudomonas aeruginosa infection, key hallmarks of the disease.
VX-770 and VX-809 are small molecule drugs designed to increase CFTR function. VX-770 is a potentiator of CFTR activity and VX-809 acts as a pharmacochaperone that has been shown to rescue expression of the CFTR-ΔF508 mutant that is susceptible to misfolding. VX-809 is active in an enzyme fragment complementation (EFC)-based assay for pharmacotrafficking that detects increased cell surface levels of CFTR-ΔF508.
In order to characterize biological activities of VX-770 and VX-809 that might be relevant for clinical efficacy, we profiled VX-770 and VX-809 across a standardized panel of human primary cell based disease models (BioMAP Diversity PLUS® panel). Several bioactivities that are directly associated with disease mechanisms in cystic fibrosis were identified. These include inhibition of PGE2 in a monocyte-driven model of inflammation, decreased IL-17F in a model of T cell-dependent B cell activation, and decreased Eotaxin-3 in a model of epithelial cell responses. PGE2 is known to drive overproduction of mucous in CF patients; IL-17F is a Th17 cytokine associated with epithelial inflammation; and Eotaxin-3 is a chemokine associated with helper Th2-type immune responses. This pattern of activities is consistent with inhibition of Th17 and Th2-type responses, and is also associated with protection against Pseudomonas aeruginosa. Interestingly, analysis of a large reference database for drugs that are phenotypically similar to VX-809 across the BioMAP assay panel identified ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) that slows disease in CF patients. Both compounds decrease levels of PGE2 in a monocyte inflammation model. These results show how profiling across a standardized panel of human primary cell systems leads to increased understanding of drug mechanisms relevant to pathologic disease processes. The assays and bioactivities identified may be useful for the characterization and comparison of new drugs. These in vitro assays are also highly suitable for testing of drug combinations.