Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG)

Kristin E. Finch, Claire Knezevic, Amanda C. Nottbohm, Kathryn C. Partlow, Paul J. Hergenrother

Research output: Contribution to journalArticle

Abstract

The poly(ADP-ribose) (PAR) post-translational modification is essential for diverse cellular functions, including regulation of transcription, response to DNA damage, and mitosis. Cellular PAR is predominantly synthesized by the enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a critical node in the DNA damage response pathway, and multiple potent PARP-1 inhibitors have been described, some of which show considerable promise in the clinic for the treatment of certain cancers. Cellular PAR is efficiently degraded by poly(ADP-ribose) glycohydrolase (PARG), an enzyme for which no potent, readily accessible, and specific inhibitors exist. Herein we report the discovery of small molecules that effectively inhibit PARG in vitro and in cellular lysates. These potent PARG inhibitors can be produced in two chemical steps from commercial starting materials and have complete specificity for PARG over the other known PAR glycohydrolase (ADP-ribosylhydrolase 3, ARH3) and over PARP-1 and thus will be useful tools for studying the biochemistry of PAR signaling.

Original languageEnglish (US)
Pages (from-to)563-570
Number of pages8
JournalACS Chemical Biology
Volume7
Issue number3
DOIs
StatePublished - Mar 16 2012
Externally publishedYes

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Poly(ADP-ribose) Polymerases
ADP-ribosylarginine hydrolase
Molecules
DNA Damage
Poly Adenosine Diphosphate Ribose
Biochemistry
Glycoside Hydrolases
DNA
Enzymes
Transcription
Post Translational Protein Processing
Mitosis
poly ADP-ribose glycohydrolase
Poly (ADP-Ribose) Polymerase-1
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Finch, K. E., Knezevic, C., Nottbohm, A. C., Partlow, K. C., & Hergenrother, P. J. (2012). Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). ACS Chemical Biology, 7(3), 563-570. https://doi.org/10.1021/cb200506t

Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). / Finch, Kristin E.; Knezevic, Claire; Nottbohm, Amanda C.; Partlow, Kathryn C.; Hergenrother, Paul J.

In: ACS Chemical Biology, Vol. 7, No. 3, 16.03.2012, p. 563-570.

Research output: Contribution to journalArticle

Finch, KE, Knezevic, C, Nottbohm, AC, Partlow, KC & Hergenrother, PJ 2012, 'Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG)', ACS Chemical Biology, vol. 7, no. 3, pp. 563-570. https://doi.org/10.1021/cb200506t
Finch, Kristin E. ; Knezevic, Claire ; Nottbohm, Amanda C. ; Partlow, Kathryn C. ; Hergenrother, Paul J. / Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). In: ACS Chemical Biology. 2012 ; Vol. 7, No. 3. pp. 563-570.
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