Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.

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Lehtio L, Jemth AS, Collins R, Loseva O, Johansson A, Markova N, Hammarstrom M, Flores A, Holmberg-Schiavone L, Weigelt J, Helleday T, Schuler H, Karlberg T

Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3.

J Med Chem. 2009 May 14;52(9):3108-11. doi: 10.1021/jm900052j.

PubMed ID

19354255 [ View in PubMed

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Abstract

Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-[3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one	Poly [ADP-ribose] polymerase 3	Kd (nM)	70	N/A	N/A	Details
N~2~,N~2~-DIMETHYL-N~1~-(6-OXO-5,6-DIHYDROPHENANTHRIDIN-2-YL)GLYCINAMIDE	Poly [ADP-ribose] polymerase 3	Kd (nM)	700	N/A	N/A	Details