PARG Inhibition

Poly(ADP-ribose) (PAR) is synthesized by the enzyme PARP-1 in response to DNA damage. The enzyme poly (ADP-ribose) glycohydrolase (PARG) cleaves PAR down to smaller PAR chains and ultimately to ADP-ribose. Inhibitors of PARP-1 and PARG thus can disrupt the normal process of DNA damage repair, and therefore have potential as antitumor drugs either alone or in combination with DNA damaging agents. We are actively synthesizing novel PARG substrates and inhibitors and using these compounds as tools to interrogate PARG inhibition as an anticancer strategy.

Diagram of PAR Metabolism.

PAR Metabolism


Related Publications

  1. Structural analyses of NudT16–ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins
    Thirawatananond, P.; McPherson, R. L.; Malhi, J.; Nathan, S.; Lambrecht, M.J.; Brichacek, M.; Hergenrother, P.J.; Leung, A.K.L.; Gabelli, S.B.
    Sci. Reports20199, 5940

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  1. (ADP-ribosyl)hydrolases: Structural basis for differential substrate recognition and inhibition
    Rack, J.G.M.; Ariza, A.; Drown, B. S.; Henfrey, C.; Shirai, T.; Hergenrother, P. J.; Ahel, I.
    Cell Chem. Biol. 201825, 1533-1546

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  1. Monitoring poly(ADP-ribosyl)glycohydrolase activity with a continuous fluorescent substrate
    Drown, B. S.; Shirai, T.; Rack, J.G.M.; Ahel, I.; Hergenrother, P. J.
    Cell Chem. Biol. 201825, 1562-1570

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  1. Synthesis of Dimeric ADP-Ribose and Its Structure with Human Poly(ADP-Ribose) Glycohydrolase
    Lambrecht, M. J.; Brichacek, M.; Barkauskaite, E.; Ariza, A.; Ahel, I.; Hergenrother, P. J.  
    J. Am. Chem. Soc. 2015137, 3558-3564.

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  1. Structure and Mechanism of a Canonical Poly(ADP-Ribose) Glycohydrolase
    Dunstan, M. S.; Barkauskaite, E.; Lafite, P.; Knezevic, C. E.; Brassington, A.; Ahel, M.; Hergenrother, P. J.; Leys, D.; Ahel, I. 
    Nat. Commun. 20123, 878.

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  1. Selective Small Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG)
    Finch, K. E.; Knezevic, C. E.; Nottbohm, A. C.; Partlow, K. C.; Hergenrother, P. J.
    ACS Chem. Biol. 20127, 563-570.

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    Meet the Authors

  1. Poly(ADP-Ribose) Makes a Date with Death
    Heeres, J. T.; Hergenrother, P. J.
    Curr. Opin. Chem. Biol. 200711, 644-653.

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  1. The Promises and Pitfalls of Small-Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG)
    Nottbohm, A. C.; Hergenrother, P. J.
    Drug Discovery Research: New Frontiers in the Post-Genomic Era 2007, 163-185.
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