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

Abstract

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, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 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 DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (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 DGG200064 as a novel oral anti-colorectal cancer drug.

Targeted variant prevalence of FBXW7 gene mutation in colorectal carcinoma propagation. The first systematic review and meta-analysis

“…Similar to the APC, BRAF, and KRAS genes, the FBXW7 gene aberrations are commonly identified in many cancer types, identified in about 5–10 % of all sequenced cancer cases [ [13] , [14] , [15] , [16] ], approximately 5–7% in CRCs [ 17 ], 30 % in cholangiocarcinoma [ 13 ], and 15 % in hepatic cancer [ 18 , 19 ]. An important pitfall hindering cancer-sequencing exploration is the limited headway to substantively detect variant genes with reduced recurrence mutation rate “i.e.…”