Development and structural analysis of adenosine site binding tankyrase inhibitors

Bioorg Med Chem Lett. 2016 Jan 15;26(2):328-333. doi: 10.1016/j.bmcl.2015.12.018. Epub 2015 Dec 8.


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.

Keywords: ARTD; PARP; Small-molecule; Tankyrase; Tankyrase inhibitor; WNT inhibitor; WNT signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / chemistry*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Catalytic Domain
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Tankyrases / antagonists & inhibitors*
  • para-Aminobenzoates / chemical synthesis
  • para-Aminobenzoates / chemistry*
  • para-Aminobenzoates / pharmacology


  • Antineoplastic Agents
  • JW55 compound
  • para-Aminobenzoates
  • TNKS2 protein, human
  • Tankyrases
  • TNKS protein, human
  • Adenosine