Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

J Med Chem. 2020 Apr 23;63(8):4183-4204. doi: 10.1021/acs.jmedchem.0c00045. Epub 2020 Apr 1.


Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology
  • Drug Design*
  • Drug Discovery / methods*
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / chemistry
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Protein Structure, Tertiary
  • Rats
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / chemistry
  • Tankyrases / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays / methods


  • Enzyme Inhibitors
  • TNKS2 protein, human
  • Tankyrases