Development and structural analysis of adenosine site binding tankyrase inhibitors

Teemu Haikarainen, Jo Waaler, Alexander Ignatev, Yves Nkizinkiko, Harikanth Venkannagari, Ezeogo Obaji, Stefan Krauss, Lari Lehtiö

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.

Original languageEnglish (US)
Pages (from-to)328-333
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Issue number2
StatePublished - Jan 15 2016
Externally publishedYes


  • ARTD
  • PARP
  • Small-molecule
  • Tankyrase
  • Tankyrase inhibitor
  • WNT inhibitor
  • WNT signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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