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

Area of Science:

• Pharmacology and Drug Discovery
• Oncology and Cancer Research
• Translational Medicine

Background:

• Drug repositioning aims to find new uses for existing drugs, but often faces high failure rates in late-stage clinical trials.
• Kinase inhibitors are a key class of drugs, with many evaluated for repositioning across various diseases.

Purpose of the Study:

• To develop a predictive metric for drug repositioning success by measuring effective drug exposure.
• To reduce the clinical failure rate in drug repurposing studies for kinase inhibitors.

Main Methods:

• Data mining was used to analyze 139 repositioning hypotheses for 11 approved kinase inhibitors.
• An in vitro pharmacodynamic assay was developed, incorporating human serum proteins to measure effective drug exposure.
• The predictive power of this metric was validated across multiple kinase inhibitors and cancer types (leukemia, NSCLC, GISTs).

Main Results:

• The developed metric of effective drug exposure was highly predictive of clinical activity for five kinase inhibitors in leukemia.
• Model performance was further validated in six additional kinase inhibitors for non-small cell lung cancer (NSCLC) and gastrointestinal stromal tumors (GISTs).
• The approach demonstrated a significant improvement in predicting clinical efficacy compared to traditional repositioning efforts.

Conclusions:

• Measuring effective drug exposure using a corrected in vitro assay is a straightforward and effective strategy to improve drug repositioning success.
• This method can decrease the clinical failure rate, making drug repurposing a more reliable strategy for developing new cancer therapies.