Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor
- Authors
- Ryu, Hwani; Nam, Ky-Youb; Kim, Hyo Jeong; Song, Jie-Young; Hwang, Sang-Gu; Kim, Jae Sung; Kim, Joon; Ahn, Jiyeon
- Issue Date
- 7월-2021
- Publisher
- MDPI
- Keywords
- WNT/beta-catenin pathway; colorectal cancer; combination therapy; tankyrase; tankyrase inhibitor
- Citation
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.22, no.14
- Indexed
- SCIE
SCOPUS
- Journal Title
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
- Volume
- 22
- Number
- 14
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/137215
- DOI
- 10.3390/ijms22147330
- ISSN
- 1661-6596
- Abstract
- More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/beta-catenin activation. Tankyrase (TNKS) mediates the release of active beta-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 beta-catenin, and downregulated beta-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.
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