PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3.

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

[1]  N. Pannu,et al.  REFMAC5 for the refinement of macromolecular crystal structures , 2011, Acta crystallographica. Section D, Biological crystallography.

[2]  J. Pascal,et al.  The Zn3 Domain of Human Poly(ADP-ribose) Polymerase-1 (PARP-1) Functions in Both DNA-dependent Poly(ADP-ribose) Synthesis Activity and Chromatin Compaction* , 2010, The Journal of Biological Chemistry.

[3]  Clemens Vonrhein,et al.  Data processing and analysis with the autoPROC toolbox , 2011, Acta crystallographica. Section D, Biological crystallography.

[4]  C. Koch,et al.  The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair , 2013, Nucleic acids research.

[5]  Simon Messner,et al.  Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites , 2009, Nucleic acids research.

[6]  V. Schreiber,et al.  Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression , 2011, Proceedings of the National Academy of Sciences.

[7]  J. Weigelt,et al.  Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors , 2012, Nature Biotechnology.

[8]  A. Ashworth,et al.  The DNA damage response and cancer therapy , 2012, Nature.

[9]  H. Schüler,et al.  Crystal Structure of Human ADP-ribose Transferase ARTD15/PARP16 Reveals a Novel Putative Regulatory Domain* , 2012, The Journal of Biological Chemistry.

[10]  F. Dantzer,et al.  PARP-3, a DNA-dependent PARP with emerging roles in double-strand break repair and mitotic progression , 2011, Cell cycle.

[11]  J. Weigelt,et al.  Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3. , 2009, Journal of medicinal chemistry.

[12]  B. Reina-San-Martin,et al.  PARP-3 and APLF function together to accelerate nonhomologous end-joining. , 2011, Molecular cell.

[13]  E. Salah,et al.  High throughput production of recombinant human proteins for crystallography. , 2008, Methods in molecular biology.

[14]  G. Poirier,et al.  PARP‐3 associates with polycomb group bodies and with components of the DNA damage repair machinery , 2007, Journal of cellular biochemistry.

[15]  P. Emsley,et al.  Features and development of Coot , 2010, Acta crystallographica. Section D, Biological crystallography.

[16]  Emidio Camaioni,et al.  PARP inhibitors: polypharmacology versus selective inhibition , 2013, The FEBS journal.

[17]  F. Moroni.  Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. , 2008, Current opinion in pharmacology.

[18]  T. Yap,et al.  Targeting the DNA damage response in oncology: past, present and future perspectives , 2012, Current opinion in oncology.