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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0001-6870-0677
GlaxoSmithKline, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England..
GlaxoSmithKline, Dept Target & Pathway Validat, Stevenage SG1 2NY, Herts, England..
Karolinska Inst, Div Translat Med, Labs Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol, Solna, Sweden..
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 30, p. E6231-E6239Article in journal (Refereed) Published
Abstract [en]

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 available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2017. Vol. 114, no 30, p. E6231-E6239
Keywords [en]
intracellular drug bioavailability, drug exposure, target engagement, published kinase inhibitor set, MAPK14
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-332843DOI: 10.1073/pnas.1701848114ISI: 000406189900026PubMedID: 28701380OAI: oai:DiVA.org:uu-332843DiVA, id: diva2:1155730
Funder
Swedish Research Council, 2822Carl Tryggers foundation Magnus Bergvall FoundationÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, FP7, Seventh Framework Programme, 607517Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2018-01-13Bibliographically approved

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Mateus, AndréMatsson, PärArtursson, Per

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