Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.

ABSTRACT: Drug repositioning seeks to leverage existing clinical knowledge to identify alternative clinical settings for approved drugs. However, repositioning efforts fail to demonstrate improved success rates in late-stage clinical trials. Focusing on 11 approved kinase inhibitors that have been evaluated in 139 repositioning hypotheses, we use data mining to characterize the state of clinical repurposing. Then, using a simple experimental correction with human serum proteins in in vitro pharmacodynamic assays, we develop a measurement of a drug's effective exposure. We show that this metric is remarkably predictive of clinical activity for a panel of five kinase inhibitors across 23 drug variant targets in leukemia. We then validate our model's performance in six other kinase inhibitors for two t

SUBMITTER: Liu C 

PROVIDER: S-EPMC10591048 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature