Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors - PubMed (original) (raw)

. 2013 Nov 20;5(1):18-22.

doi: 10.1021/ml400292s. eCollection 2014 Jan 9.

Affiliations

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Teemu Haikarainen et al. ACS Med Chem Lett. 2013.

Abstract

Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include the small general PARP inhibitors Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite of tankyrase 2. Crystal structures reveal flexibility of the ligand binding site with implications for drug development against tankyrases and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD(+) and extends from the nicotinamide to the adenosine subsite. The clinical ARTD1 inhibitor candidate rucaparib was the most potent tankyrase inhibitor identified (24 and 14 nM for tankyrases), which indicates that inhibition of tankyrases would affect the cellular responses of this compound.

Keywords: ADP-ribosyltransferase; PARP; Tankyrase; inhibitor; poly(ADP-ribose) polymerase.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Screening of PARP inhibitor compounds and the structures of the potent hit compounds. At 10 μM many of the compounds inhibited ARTD5, whereas a test at 500 nM identified 9 compounds that showed over 20% inhibition. Data shown are mean ± SD.

Figure 2

Figure 2

Crystal structures of (a) phenanthridinone (16), (b) TIQ-A (18), (c) PJ-34 (17), and (d) rucaparib (29) bound to the ARTD6 catalytic fragment. The compounds are shown as ball-and-stick models and the hydrogen bonds with the protein are shown as dashed lines. The disordered D-loop in panels c and d is shown as a thick dashed line.

Figure 3

Figure 3

Binding of the dual site inhibitor EB-47 (10) and comparison of the structure with the substrate NAD+ binding mode to Diphtheria toxin. (a) Binding mode of EB-47 to ARTD6. (b) Comparison of superposed EB-47 with NAD+ bound to Diphtheria toxin (PDB code 1TOX). Superposition was done with selected atoms in order to overlap adenosine and nicotinamide moieties. (c) NAD+ complex conformation observed in Diphtheria toxin (PDB code 1TOX). The disordered D-loop is shown as a dashed line.

Similar articles

Cited by

References

    1. Bryant H. E.; Schultz N.; Thomas H. D.; Parker K. M.; Flower D.; Lopez E.; Kyle S.; Meuth M.; Curtin N. J.; Helleday T. Specific Killing of BRCA2-Deficient Tumours with Inhibitors of Poly(ADP-ribose) Polymerase. Nature 2005, 434, 913–917. - PubMed
    1. Curtin N.; Szabo C. Therapeutic Applications of PARP Inhibitors: Anticancer Therapy and Beyond. Mol. Aspects Med. 2013, 24, 1217–1256. - PMC - PubMed
    1. De Rycker M.; Price C. M. Tankyrase Polymerization Is Controlled by Its Sterile Alpha Motif and Poly(ADP-ribose) Polymerase Domains. Mol. Cell. Biol. 2004, 24, 9802–9812. - PMC - PubMed
    1. Riffell J. L.; Lord C. J.; Ashworth A. Tankyrase-Targeted Therapeutics: Expanding Opportunities in the PARP Family. Nat. Rev. Drug Discovery 2012, 11, 923–936. - PubMed
    1. Lehtiö L.; Chi N.-W.; Krauss S. Tankyrases as Drug Targets. FEBS J. 2013, 280, 3576–3593. - PubMed

LinkOut - more resources