<abstract xmlns="http://www.w3.org/1999/xhtml">
Colorectal cancer (CRC) is one of the most common types of malignant cancers worldwide. Although molecularly targeted therapies have significantly improved treatment outcomes, most of these target inhibitors are resistant. Novel inhibitors as potential anticancer drug candidates are still needed to be discovered. Therefore, in the present study, we synthesized a novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative (compound <bold>4</bold>) using fragment- and structure-based techniques and then investigated the anticancer effect and underlying mechanism of anti-CRC. The results revealed that compound <bold>4</bold> significantly inhibited HCT116 cell proliferation with <italic>IC</italic>50 values of 8.04 ± 0.94 µmol L–1 after 48 h and 5.52 ± 0.42 µmol L–1 after 72 h, respectively. Compound <bold>4</bold> also inhibited colony formation, migration, and invasion of HCT116 cells in a dose-dependent manner, as well as inducing cell apoptosis and arresting the cell cycle in the G2/M phase. In addition, compound <bold>4</bold> was able to inhibit the activation of the MEK/ERK signaling in HCT116 cells. And compound <bold>4</bold> yielded the same effects as the MEK inhibitor U0126 on cell apoptosis and MEK/ERK-related proteins. These findings suggested that compound <bold>4</bold> inhi bited cell proliferation and growth, and induced cell apoptosis, indicating its use as a novel and potent anticancer agent against CRC <italic>via</italic> the MEK/ERK signaling pathway.
</abstract>

Colorectal cancer (CRC) is one of the most common types of malignant cancers worldwide. Although molecularly targeted therapies have significantly improved treatment outcomes, most of these target inhibitors are resistant.  Novel inhibitors as potential anticancer drug candidates are still needed to be discovered. Therefore, in the present study, we synthesized a novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative (compound 4) using fragment- and structure-based techniques and then investigated the anticancer effect and underlying mechanism of anti-CRC. The results revealed that compound 4 significantly inhibited HCT116 cell proliferation with IC50 values of 8.04 ± 0.94 µmol L–1 after 48 h and 5.52 ± 0.42 µmol L–1 after 72 h, respectively. Compound 4 also inhibited colony formation, migration, and invasion of HCT116 cells in a dose-dependent manner, as well as inducing cell apoptosis and arresting the cell cycle in the G2/M phase. In addition, compound 4 was able to  inhibit the activation of the MEK/ERK signaling in HCT116 cells. And compound 4 yielded the same effects as the MEK inhibitor U0126 on cell apoptosis and MEK/ERK-related proteins. These findings suggested that compound 4 inhi bited cell proliferation and growth, and induced cell apoptosis, indicating its use as a novel and potent anticancer agent against CRC via the MEK/ERK signaling pathway.

A novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative inhibits cell proliferation by suppressing the MEK/ERK signaling pathway in colorectal cancer

The Second Affiliated Hospital of Xi’an Medical University

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Colorectal cancer (CRC) is one of the most common types of malignant cancers worldwide. Although molecularly targeted therapies have significantly improved...

A novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative inhibits cell proliferation by suppressing the MEK/ERK signaling pathway in colorectal cancer

Published Online: Sep 14, 2023

Page range: 489 - 502

Accepted: Apr 18, 2023

DOI: https://doi.org/10.2478/acph-2023-0025

Keywords
colorectal cancer, proliferation, apoptosis, meta-stasis, MEK/ERK signaling pathway

© 2023 Weiwei Li et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

A novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative inhibits cell proliferation by suppressing the MEK/ERK signaling pathway in colorectal cancer

Published Online: Sep 14, 2023

Page range: 489 - 502

Accepted: Apr 18, 2023

DOI: https://doi.org/10.2478/acph-2023-0025

Keywordscolorectal cancer, proliferation, apoptosis, meta-stasis, MEK/ERK signaling pathway

© 2023 Weiwei Li et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
colorectal cancer, proliferation, apoptosis, meta-stasis, MEK/ERK signaling pathway