TY - JOUR
T1 - Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets
AU - Knezevic, Claire E.
AU - Wright, Gabriela
AU - Remsing Rix, Lily L.
AU - Kim, Woosuk
AU - Kuenzi, Brent M.
AU - Luo, Yunting
AU - Watters, January M.
AU - Koomen, John M.
AU - Haura, Eric B.
AU - Monteiro, Alvaro N.
AU - Radu, Caius
AU - Lawrence, Harshani R.
AU - Rix, Uwe
N1 - Funding Information:
This work was supported by the H. Lee Moffitt Cancer Center and Research Institute, Miles for Moffitt, and the V Foundation. We furthermore wish to acknowledge the Moffitt Chemical Biology (Chemistry Unit) and Proteomics Core Facilities, which are supported by the National Cancer Institute (Award no. P30-CA076292) as a Cancer Center Support Grant. Proteomics is also supported by the Moffitt Foundation and the Bankhead-Coley Cancer Research program of the Florida Department of Health (09BE-04). C.R. and W.K. were supported by a National Cancer Institute Grant R01 CA187678. C.R. is among the inventors of intellectual property for unrelated small-molecule DCK inhibitors which have been licensed by the University of California to Trethera Corporation in which C.R. holds equity.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/12/22
Y1 - 2016/12/22
N2 - 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.
AB - 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.
KW - H6PD
KW - PARP inhibitor
KW - chemical proteomics
KW - polypharmacology
KW - target identification
KW - target selectivity
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U2 - 10.1016/j.chembiol.2016.10.011
DO - 10.1016/j.chembiol.2016.10.011
M3 - Article
AN - SCOPUS:85027933448
SN - 2451-9448
VL - 23
SP - 1490
EP - 1503
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 12
ER -