Discovery of a novel triazolopyridine derivative as a tankyrase inhibitor

Hwani Ryu, Ky Youb Nam, Hyo Jeong Kim, Jie Young Song, Sang Gu Hwang, Jae Sung Kim, Joon Kim, Jiyeon Ahn

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.

Original languageEnglish
Article number7330
JournalInternational journal of molecular sciences
Issue number14
Publication statusPublished - 2021 Jul 2

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Colorectal cancer
  • Combination therapy
  • Tankyrase
  • Tankyrase inhibitor
  • WNT/β-catenin pathway

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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