In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 30 ( 2017-07-25)
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 available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1701848114
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2017
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink