Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

J Med Chem. 2021 Dec 23;64(24):17936-17949. doi: 10.1021/acs.jmedchem.1c01264. Epub 2021 Dec 8.


Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC50 inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Development*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Hippo Signaling Pathway / drug effects
  • Humans
  • Mice
  • Structure-Activity Relationship
  • Tankyrases / antagonists & inhibitors*
  • Triazoles / chemistry
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Wnt Signaling Pathway / drug effects


  • Enzyme Inhibitors
  • Triazoles
  • 1,2,4-triazole
  • Tankyrases