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

doi:10.1016/j.chembiol.2016.10.011

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^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

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 language	English (US)
Pages (from-to)	1490-1503
Number of pages	14
Journal	Cell Chemical Biology
Volume	23
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2016.10.011
State	Published - Dec 22 2016

Funding

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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2016.10.011

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Knezevic, C. E., Wright, G., Remsing Rix, L. L., Kim, W., Kuenzi, B. M., Luo, Y., Watters, J. M., Koomen, J. M., Haura, E. B., Monteiro, A. N., Radu, C., Lawrence, H. R., & Rix, U. (2016). Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets. Cell Chemical Biology, 23(12), 1490-1503. https://doi.org/10.1016/j.chembiol.2016.10.011

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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