Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets. Issue 12 (22nd December 2016)

• Record Type: Journal Article
• Authors: Knezevic, Claire E.; Wright, Gabriela; Remsing Rix, Lily L.; Kim, Woosuk; Kuenzi, Brent M.; Luo, Yunting; Watters, January M.; Koomen, John M.; Haura, Eric B.; Monteiro, Alvaro N.; Radu, Caius; Lawrence, Harshani R.; Rix, Uwe
• Is Part Of: Cell chemical biology. Volume 23:Issue 12(2016)
• Page Start: 1490
• Page End: 1503
• Publication Date: 2016-12-22
• Subjects: chemical proteomics -- PARP inhibitor -- target identification -- target selectivity -- H6PD -- polypharmacology; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.10.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively. Subsequent functional validation suggested that inhibition of DCK by niraparib could have detrimental effects when combined with nucleoside analog pro-drugs. H6PD silencing can cause apoptosis and further sensitize cells to PARPi, suggesting that H6PD may be, in addition to its established role in metabolic disorders, a new anticancer target. Graphical Abstract: Highlights: Clinical PARP inhibitors display differential proteome-wide target selectivity PARP inhibitors as a class have high target selectivity Hexose-6-phosphate dehydrogenase (H6PD) is a new cancer-relevant rucaparib target Deoxycytidine kinase (DCK) is a new context-dependent anti-target of niraparib Abstract : Knezevic et al. describe the first side-by-side and proteome-wide target profile characterization of four clinical PARP1 inhibitors. Whereas olaparib and veliparib display a high level of specificity for PARP1/2, rucaparib and niraparib also inhibit the non-canonical, cancer-relevant targets H6PD and DCK, respectively.