Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-<i>b</i>]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest

• Main Authors: Eun-Sil Lee (Author), Nayeon Kim (Author), Joon Hee Kang (Author), Aizhan Abdildinova (Author), Seon-Hyeong Lee (Author), Myung Hwi Lee (Author), Nam Sook Kang (Author), Tae-Sung Koo (Author), Soo-Youl Kim (Author), Young-Dae Gong (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, <b>DGG200064</b> (<b>7c</b>) with a 2-alkoxythieno [2,3-<i>b</i>]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound <b>DGG200064</b> was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized <b>DGG200064</b> inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, <b>DGG200064</b> (GI₅₀ = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of <b>DGG200064</b> as a novel oral anti-colorectal cancer drug.

Item Description

10.3390/ph15050502
1424-8247