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

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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; Löw, Mirjam; Pinto, Ana Filipa; Trésaugues, Lionel; Moche, Martin; Cohen, Michael S; Schüler, Herwig.

in: J MED CHEM, Jahrgang 60, Nr. 4, 23.02.2017, S. 1262-1271.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Thorsell, A-G, Ekblad, T, Karlberg, T, Löw, M, Pinto, AF, Trésaugues, L, Moche, M, Cohen, MS & Schüler, H 2017, 'Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors', J MED CHEM, Jg. 60, Nr. 4, S. 1262-1271. https://doi.org/10.1021/acs.jmedchem.6b00990

APA

Thorsell, A-G., Ekblad, T., Karlberg, T., Löw, M., Pinto, A. F., Trésaugues, L., Moche, M., Cohen, M. S., & Schüler, H. (2017). Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. J MED CHEM, 60(4), 1262-1271. https://doi.org/10.1021/acs.jmedchem.6b00990

Vancouver

Thorsell A-G, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L et al. Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. J MED CHEM. 2017 Feb 23;60(4):1262-1271. https://doi.org/10.1021/acs.jmedchem.6b00990

Bibtex

@article{9f3d60c66bc94b738dca8f9572d203a8,
title = "Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors",
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 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.",
keywords = "Animals, Benzimidazoles, Enzyme Inhibitors, HEK293 Cells, Humans, Indazoles, Models, Molecular, Phenanthrenes, Phthalazines, Piperazines, Piperidines, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Tankyrases, Journal Article",
author = "Ann-Gerd Thorsell and Torun Ekblad and Tobias Karlberg and Mirjam L{\"o}w and Pinto, {Ana Filipa} and Lionel Tr{\'e}saugues and Martin Moche and Cohen, {Michael S} and Herwig Sch{\"u}ler",
year = "2017",
month = feb,
day = "23",
doi = "10.1021/acs.jmedchem.6b00990",
language = "English",
volume = "60",
pages = "1262--1271",
journal = "J MED CHEM",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

RIS

TY - JOUR

T1 - Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

AU - Thorsell, Ann-Gerd

AU - Ekblad, Torun

AU - Karlberg, Tobias

AU - Löw, Mirjam

AU - Pinto, Ana Filipa

AU - Trésaugues, Lionel

AU - Moche, Martin

AU - Cohen, Michael S

AU - Schüler, Herwig

PY - 2017/2/23

Y1 - 2017/2/23

N2 - 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.

AB - 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.

KW - Animals

KW - Benzimidazoles

KW - Enzyme Inhibitors

KW - HEK293 Cells

KW - Humans

KW - Indazoles

KW - Models, Molecular

KW - Phenanthrenes

KW - Phthalazines

KW - Piperazines

KW - Piperidines

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Poly(ADP-ribose) Polymerases

KW - Tankyrases

KW - Journal Article

U2 - 10.1021/acs.jmedchem.6b00990

DO - 10.1021/acs.jmedchem.6b00990

M3 - SCORING: Journal article

C2 - 28001384

VL - 60

SP - 1262

EP - 1271

JO - J MED CHEM

JF - J MED CHEM

SN - 0022-2623

IS - 4

ER -