Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets

Claire E. Knezevic, Gabriela Wright, Lily L. Remsing Rix, Woosuk Kim, Brent M. Kuenzi, Yunting Luo, January M. Watters, John M. Koomen, Eric B. Haura, Alvaro N. Monteiro, Caius Radu, Harshani R. Lawrence, Uwe Rix

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1490-1503
Number of pages14
JournalCell Chemical Biology
Volume23
Issue number12
DOIs
StatePublished - Dec 22 2016

Keywords

  • H6PD
  • PARP inhibitor
  • chemical proteomics
  • polypharmacology
  • target identification
  • target selectivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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