Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors
(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.
(Less)
- author
- Thorsell, Ann-Gerd
; Ekblad, Torun
; Karlberg, Tobias
LU
; Löw, Mirjam
; Pinto, Ana Filipa
; Trésaugues, Lionel
; Moche, Martin
; Cohen, Michael S
and Schüler, Herwig
LU
- publishing date
- 2017-02-23
- 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
-
- pmid:28001384
- scopus:85013828471
- 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}}, }