Exploiting Polypharmacology in Precision Oncology: Identification of Differential Kinase Off-targets Among Clinical PARP Inhibitors
A more comprehensive and systems-based approach to pharmacology is uncovering that drugs tend to bind to more than one target, a behaviour commonly referred to as polypharmacology with clinical implications that are still not well understood.1
The increasing availability of ligand-target interaction data in the public domain in resources such as canSAR2 enables the development of computational methods to predict polypharmacology, that are becoming a cost-effective means to uncover new targets of drugs. PARP inhibitors are a new class of targeted small-molecule cancer therapeutics that have shown unexplained differential effects in cellular models and clinical trials.3
Can we use computational methods to identify previously unknown off-targets of PARP inhibitors that can explain their observed differences?
References
(1) Jalencas X, Mestres J. On the origins of drug polypharmacology. Med. Chem. Commun.,4, 80-87 (2013).
(2) Tym JE, Mitsopoulos C, Coker EA, Razaz P, Schierz AC, Antolin AA, Al-Lazikani B. CanSAR: updated cancer research and drug discovery knowledgebase. Nucleic Acids Res. 44, D938-43 (2016).
(3) Antolín AA, Mestres J. Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors. Oncotarget. 5, 3023-8 (2014).
