A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity

Ilsa T. Kirby, Ana Kojic, Moriah R. Arnold, Ann Gerd Thorsell, Tobias Karlberg, Anke Vermehren-Schmaedick, Raashi Sreenivasan, Carsten Schultz, Herwig Schüler, Michael Cohen

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.

Original languageEnglish (US)
Pages (from-to)1547-1553.e12
JournalCell Chemical Biology
Volume25
Issue number12
DOIs
StatePublished - Dec 20 2018

Fingerprint

Adenosine Diphosphate
Catalyst activity
Nuclear Envelope
Poly(ADP-ribose) Polymerases
Availability
Imaging techniques
Molecules
Poly(ADP-ribose) Polymerase Inhibitors

Keywords

  • ADP-ribosylation
  • MARylation
  • nuclear envelope
  • PARP11
  • PARPs

ASJC Scopus subject areas

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

Cite this

Kirby, I. T., Kojic, A., Arnold, M. R., Thorsell, A. G., Karlberg, T., Vermehren-Schmaedick, A., ... Cohen, M. (2018). A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity. Cell Chemical Biology, 25(12), 1547-1553.e12. https://doi.org/10.1016/j.chembiol.2018.09.011

A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity. / Kirby, Ilsa T.; Kojic, Ana; Arnold, Moriah R.; Thorsell, Ann Gerd; Karlberg, Tobias; Vermehren-Schmaedick, Anke; Sreenivasan, Raashi; Schultz, Carsten; Schüler, Herwig; Cohen, Michael.

In: Cell Chemical Biology, Vol. 25, No. 12, 20.12.2018, p. 1547-1553.e12.

Research output: Contribution to journalArticle

Kirby, IT, Kojic, A, Arnold, MR, Thorsell, AG, Karlberg, T, Vermehren-Schmaedick, A, Sreenivasan, R, Schultz, C, Schüler, H & Cohen, M 2018, 'A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity', Cell Chemical Biology, vol. 25, no. 12, pp. 1547-1553.e12. https://doi.org/10.1016/j.chembiol.2018.09.011
Kirby IT, Kojic A, Arnold MR, Thorsell AG, Karlberg T, Vermehren-Schmaedick A et al. A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity. Cell Chemical Biology. 2018 Dec 20;25(12):1547-1553.e12. https://doi.org/10.1016/j.chembiol.2018.09.011
Kirby, Ilsa T. ; Kojic, Ana ; Arnold, Moriah R. ; Thorsell, Ann Gerd ; Karlberg, Tobias ; Vermehren-Schmaedick, Anke ; Sreenivasan, Raashi ; Schultz, Carsten ; Schüler, Herwig ; Cohen, Michael. / A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 12. pp. 1547-1553.e12.
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