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Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors


Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.

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Figure 1: Compound profiling study of human PARP catalytic domains.
Figure 2: Key features of PARP catalytic domain ligand interactions from X-ray crystal structures.
Figure 3: Crystal structures of TNKS2 and PARP14 ligand complexes.

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The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from the Canadian Institutes for Health Research, the Canada Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. The study was also supported by grant RBc08-0014 from the Swedish Foundation for Strategic Research.

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E.W., T.K., E.K., N.M., A.-G.T., E.P., Å.F., T.E., B.K., H.S. and J.W. designed research; E.W., T.K., E.K., N.M., A.M., A.G.T., E.P., Å.F., T.E. and D.Ö. performed research; E.W., T.K., E.K., N.M., A.M., E.P., T.E., G.M.R., R.P., H.S. and J.W. analyzed data; and T.K., A.M., E.P., H.S. and J.W. wrote the paper.

Corresponding author

Correspondence to Herwig Schüler.

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Competing interests

N.M., E.P. and Å.F. are employees of GE Healthcare, which manufactures and markets the Biacore T-200 instrument that was used in the study.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1,2, 4–13, Supplementary Notes 1–4 and Supplementary Figs. 1–10 (PDF 1391 kb)

Supplementary Table 3

Results from the DSF screen and compound information. (XLSX 101 kb)

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Wahlberg, E., Karlberg, T., Kouznetsova, E. et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 30, 283–288 (2012).

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