Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery.

ABSTRACT: Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F_ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F_ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F_ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally availab

SUBMITTER: Mateus A 

PROVIDER: S-EPMC5544291 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature