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.

Figure 1. Chemical structures of PARP inhibitors including the PARP drug candidates rucaparib, veliparib and olaparib (left)

The benzamide moiety that characterizes all PARP inhibitor structures is highlighted in bold. Schematic representation of the benzamide binding to both S6K1 kinase (PDB 4C35), depicted in black, and PARP-1 (PDB 2RD6), depicted in grey (right).

Figure 2. Pharmacological profile of olaparib, veliparib and rucaparib across 29 proteins, including 13 PARPs and 16 kinases

PARP data is from Ref. (9); kinase data is from this work. Dose-response curves are available in the supplementary data for the 11 kinase interactions identified with pIC₅₀ values above 4.5.

Figure 3. Dose-response curves of the in vitro affinity of rucaparib (left) and veliparib (right) with PIM1 kinase