The kinase polypharmacology landscape of clinical PARP inhibitors

Area of Science:

• Pharmacology
• Oncology
• Biochemistry

Background:

• Polypharmacology significantly influences drug response and adverse effects.
• Four FDA-approved PARP inhibitors are used in cancer therapy, but a clear mechanistic rationale for clinical selection is missing.
• Existing knowledge of PARP inhibitor polypharmacology is limited, particularly regarding off-target effects within the kinome.

Purpose of the Study:

• To comprehensively characterize the off-target kinase landscape of four FDA-approved PARP inhibitors.
• To identify unique polypharmacological profiles for each PARP inhibitor.
• To investigate potential implications of off-target kinase inhibition for clinical efficacy and safety.

Main Methods:

• Utilized kinome profiling to assess the off-target activity of four FDA-approved PARP inhibitors.
• Quantified inhibition concentrations for identified off-target kinases.
• Compared polypharmacological profiles across the four drugs.

Main Results:

• All four PARP inhibitors exhibited distinct polypharmacological profiles across the kinome.
• Niraparib and rucaparib demonstrated potent inhibition of DYRK1s, CDK16, and PIM3 at clinically relevant concentrations.
• These kinases represent the most potent off-targets identified for PARP inhibitors to date.

Conclusions:

• The unique polypharmacology of PARP inhibitors suggests a complex interplay between on-target and off-target effects.
• DYRK1s, CDK16, and PIM3 inhibition by niraparib and rucaparib warrant further investigation for clinical relevance.
• Broad kinome profiling is recommended for future PARP inhibitor development to potentially exploit polypharmacology for improved therapeutic outcomes.