Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/14/7330 |
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| author | Hwani Ryu Ky-Youb Nam Hyo Jeong Kim Jie-Young Song Sang-Gu Hwang Jae Sung Kim Joon Kim Jiyeon Ahn |
| author_facet | Hwani Ryu Ky-Youb Nam Hyo Jeong Kim Jie-Young Song Sang-Gu Hwang Jae Sung Kim Joon Kim Jiyeon Ahn |
| author_sort | Hwani Ryu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:37:48Z |
| format | Article |
| id | doaj.art-f36c8e8883674d5f956f59d3272bf31c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:37:48Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f36c8e8883674d5f956f59d3272bf31c2023-11-22T03:56:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012214733010.3390/ijms22147330Discovery of a Novel Triazolopyridine Derivative as a Tankyrase InhibitorHwani Ryu0Ky-Youb Nam1Hyo Jeong Kim2Jie-Young Song3Sang-Gu Hwang4Jae Sung Kim5Joon Kim6Jiyeon Ahn7Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDepartment of Research Center, Pharos I&BT Co., Ltd., Anyang 14059, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaLaboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 02841, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaMore 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.https://www.mdpi.com/1422-0067/22/14/7330tankyrasetankyrase inhibitorcolorectal cancerWNT/β-catenin pathwaycombination therapy |
| spellingShingle | Hwani Ryu Ky-Youb Nam Hyo Jeong Kim Jie-Young Song Sang-Gu Hwang Jae Sung Kim Joon Kim Jiyeon Ahn Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor International Journal of Molecular Sciences tankyrase tankyrase inhibitor colorectal cancer WNT/β-catenin pathway combination therapy |
| title | Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor |
| title_full | Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor |
| title_fullStr | Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor |
| title_full_unstemmed | Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor |
| title_short | Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor |
| title_sort | discovery of a novel triazolopyridine derivative as a tankyrase inhibitor |
| topic | tankyrase tankyrase inhibitor colorectal cancer WNT/β-catenin pathway combination therapy |
| url | https://www.mdpi.com/1422-0067/22/14/7330 |
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