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Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor
Hwani Ryu1, Ky-Youb Nam2, Hyo Jeong Kim1
1Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
Abstract:
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.
Insights
A novel tankyrase inhibitor, TI-12403, effectively reduces colorectal cancer cell viability and beta-catenin activation. This compound shows promise as a potential anticancer drug, especially when combined with 5-FU.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Adenomatous polyposis coli (APC) mutations in over 80% of colorectal cancer patients activate WNT/β-catenin signaling.
- Tankyrase (TNKS) promotes active β-catenin release by degrading AXIN, making TNKS inhibition a therapeutic target.
Purpose of the Study:
- To identify novel pyridine derivatives as TNKS inhibitors.
- To evaluate the efficacy and safety of a new TNKS inhibitor, TI-12403, for colorectal cancer treatment.
Main Methods:
- In vitro evaluation of TNKS enzyme activity to identify pyridine derivatives.
- Assessing TI-12403's effects on AXIN2 stabilization, β-catenin levels, and target gene expression in colorectal cancer cell lines (COLO320DM, DLD-1).
- Evaluating TI-12403's antitumor activity in a DLD-1 xenograft mouse model and its synergy with 5-FU.
Main Results:
- N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) was identified as a novel TNKS inhibitor.
- TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in vitro.
- TI-12403 demonstrated antitumor activity in colorectal cancer cells and showed no significant toxicity in a mouse model. Combined treatment with 5-FU resulted in synergistic proliferation inhibition.
Conclusions:
- TI-12403 is a novel, selective TNKS1 inhibitor with demonstrated anticancer potential.
- TI-12403 warrants further investigation as a candidate for colorectal cancer drug development.
- Combination therapy with TI-12403 and 5-FU may offer enhanced efficacy for colorectal cancer treatment.
