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Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

Thorsell, Ann-Gerd ; Ekblad, Torun ; Karlberg, Tobias LU ; Löw, Mirjam ; Pinto, Ana Filipa ; Trésaugues, Lionel ; Moche, Martin ; Cohen, Michael S and Schüler, Herwig LU orcid (2017) In Journal of Medicinal Chemistry 60(4). p.1262-1271
Abstract

Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in... (More)

Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Benzimidazoles/chemistry, Enzyme Inhibitors/chemistry, HEK293 Cells, Humans, Indazoles/chemistry, Models, Molecular, Phenanthrenes/chemistry, Phthalazines/chemistry, Piperazines/chemistry, Piperidines/chemistry, Poly(ADP-ribose) Polymerase Inhibitors/chemistry, Poly(ADP-ribose) Polymerases/metabolism, Tankyrases/antagonists & inhibitors
in
Journal of Medicinal Chemistry
volume
60
issue
4
pages
10 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85013828471
  • pmid:28001384
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.6b00990
language
English
LU publication?
no
id
54a6b195-1d64-408e-b730-614961e6472f
date added to LUP
2024-11-21 17:51:28
date last changed
2025-07-19 13:28:06
@article{54a6b195-1d64-408e-b730-614961e6472f,
  abstract     = {{<p>Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.</p>}},
  author       = {{Thorsell, Ann-Gerd and Ekblad, Torun and Karlberg, Tobias and Löw, Mirjam and Pinto, Ana Filipa and Trésaugues, Lionel and Moche, Martin and Cohen, Michael S and Schüler, Herwig}},
  issn         = {{1520-4804}},
  keywords     = {{Animals; Benzimidazoles/chemistry; Enzyme Inhibitors/chemistry; HEK293 Cells; Humans; Indazoles/chemistry; Models, Molecular; Phenanthrenes/chemistry; Phthalazines/chemistry; Piperazines/chemistry; Piperidines/chemistry; Poly(ADP-ribose) Polymerase Inhibitors/chemistry; Poly(ADP-ribose) Polymerases/metabolism; Tankyrases/antagonists & inhibitors}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  pages        = {{1262--1271}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.6b00990}},
  doi          = {{10.1021/acs.jmedchem.6b00990}},
  volume       = {{60}},
  year         = {{2017}},
}