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Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6231-E6239. doi: 10.1073/pnas.1701848114. Epub 2017 Jul 12.

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

Author information

1
Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden.
2
Platform Technology and Science, GlaxoSmithKline, SG1 2NY Stevenage, United Kingdom.
3
Department of Target and Pathway Validation, GlaxoSmithKline, SG1 2NY Stevenage, United Kingdom.
4
Division of Translational Medicine, Laboratories for Chemical Biology, Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institute, SE-171 65 Solna, Sweden.
5
Department of Medical Biochemistry & Biophysics, Chemical Biology, Karolinska Institute, SE-171 65 Solna, Sweden.
6
Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden; Per.Artursson@farmaci.uu.se.
7
Department of Pharmacy, Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, SE-751 23 Uppsala, Sweden.

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 (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic 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. Fic 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 available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.

KEYWORDS:

MAPK14; drug exposure; intracellular drug bioavailability; published kinase inhibitor set; target engagement

PMID:
28701380
PMCID:
PMC5544291
DOI:
10.1073/pnas.1701848114
[Indexed for MEDLINE]
Free PMC Article

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