Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery.
Proc Natl Acad Sci U S A
; 114(30): E6231-E6239, 2017 07 25.
Article
em En
| MEDLINE
| ID: mdl-28701380
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.
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1
Bases de dados:
MEDLINE
Assunto principal:
Descoberta de Drogas
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Suécia