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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 LU ; Vermehren-Schmaedick, Anke ; Sreenivasan, Raashi ; Schultz, Carsten ; Schüler, Herwig LU orcid and Cohen, Michael S (2018) In Cell Chemical Biology 25(12). p.12-1553
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Biocatalysis/drug effects, HeLa Cells, Humans, Molecular Structure, Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis, Poly(ADP-ribose) Polymerases/metabolism, Protein Transport/drug effects, Quinazolinones/chemical synthesis
in
Cell Chemical Biology
volume
25
issue
12
pages
12 - 1553
publisher
Elsevier
external identifiers
  • pmid:30344052
  • scopus:85055783758
ISSN
2451-9448
DOI
10.1016/j.chembiol.2018.09.011
language
English
LU publication?
no
additional info
Copyright © 2018 Elsevier Ltd. All rights reserved.
id
48cff2fe-d1fa-4c84-bca3-ade8b06692fd
date added to LUP
2024-11-21 17:47:44
date last changed
2025-04-25 22:01:45
@article{48cff2fe-d1fa-4c84-bca3-ade8b06692fd,
  abstract     = {{<p>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.</p>}},
  author       = {{Kirby, Ilsa T and Kojic, Ana and Arnold, Moriah R and Thorsell, Ann-Gerd and Karlberg, Tobias and Vermehren-Schmaedick, Anke and Sreenivasan, Raashi and Schultz, Carsten and Schüler, Herwig and Cohen, Michael S}},
  issn         = {{2451-9448}},
  keywords     = {{Biocatalysis/drug effects; HeLa Cells; Humans; Molecular Structure; Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis; Poly(ADP-ribose) Polymerases/metabolism; Protein Transport/drug effects; Quinazolinones/chemical synthesis}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{12--1553}},
  publisher    = {{Elsevier}},
  series       = {{Cell Chemical Biology}},
  title        = {{A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity}},
  url          = {{http://dx.doi.org/10.1016/j.chembiol.2018.09.011}},
  doi          = {{10.1016/j.chembiol.2018.09.011}},
  volume       = {{25}},
  year         = {{2018}},
}