title: Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors.
abstract: PARP inhibitors hold promise as a novel class of targeted anticancer drugs. However, their true mechanism of action is still not well understood following recent reports that show marked differences in cellular effects. Here, we demonstrate that three PARP drug candidates, namely, rucaparib, veliparib, and olaparib, have a clearly different in vitro affinity profile across a panel of diverse kinases selected using a computational approach that relates proteins by ligand similarity. In this respect, rucaparib inhibits nine kinases with micromolar affinity, including PIM1, PIM2, PRKD2, DYRK1A, CDK1, CDK9, HIPK2, CK2, and ALK. In contrast, olaparib does not inhibit any of the sixteen kinases tested. In between, veliparib inhibits only two, namely, PIM1 and CDK9. The differential kinase pharmacology observed among PARP inhibitors provides a plausible explanation to their different cellular effects and offers unexplored opportunities for this drug class, but alerts also on the risk associated to transferring directly both preclinical and clinical outcomes from one PARP drug candidate to another.
authors.affiliation: Systems Pharmacology, Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Antolín
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C531549:rucaparib; C531550:olaparib