Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Masitinib, a protein kinase inhibitor, shows potential in sensitizing gemcitabine-refractory cancer cells.
• Drug resistance and toxicity are significant challenges in cancer chemotherapy.

Purpose of the Study:

• To identify the molecular target responsible for masitinib-induced sensitization to gemcitabine.
• To elucidate the mechanism by which masitinib enhances the efficacy of nucleoside analogue drugs.

Main Methods:

• Utilized a reverse proteomic approach to identify drug targets.
• Investigated the interaction between masitinib, imatinib, and deoxycytidine kinase (dCK).
• Assessed the impact on nucleoside analogue drug phosphorylation.

Main Results:

• Deoxycytidine kinase (dCK) was identified as the target mediating masitinib's sensitizing effect.
• Masitinib and other kinase inhibitors activate dCK through a conformational change.
• This activation increases the phosphorylation of prodrugs activated by dCK, enhancing their efficacy.

Conclusions:

• Masitinib exhibits a dual activity: protein kinase inhibition and nucleoside kinase activation.
• This dual action could reduce chemotherapy toxicity by allowing lower effective doses.
• The findings suggest a novel therapeutic strategy to counteract drug resistance mediated by dCK downregulation.