Colorectal Cancer (bowel cancer; colon cancer) is one of the most serious cancer diseases, with the development from colon or rectum. It is mainly due to old age and environmental factors. Although we have discovered batches of anti-cancer agents, they are still lacking. Wnt/β-Catenin signaling is a canonical Wnt pathway, regulates gene transcription. The pathway results in the increase of β-catenin in the cytoplasm and its translocation into nucleus. β-catenin functions as a coactivator of transcription factors. Dysregulation of Wnt/β-Catenin signaling occurs in various kinds of disease, such as cancer. Therefore, it is necessary to find out the inhibitors of the pathway. DK419 is a small compound, acts as a potent inhibitor of Wnt/β-catenin signaling.

In the in vitro study, DK419 blocks Wnt/β-catenin gene transcription with an IC50 of 0.19 μM. Moreover, DK419 (12.5 μM) reduces protein levels in colorectal cancer cell lines, such as Axin2, β-catenin, c-Myc, Cyclin D1 and Survivin. DK419 (1 μM) increases oxygen consumption rate, and causes phosphorylation of AMPK in colonic cells. However, DK419 shows no obvious effect on AMPK levels.

Above all, DK419 exhibits potent anti-cancer activity. It suppresses the proliferation of several colonic tumor cells, with IC50s in the range of 0.07 to 0.36 μM.

In consistence with the in vitro result, DK419 inhibits tumor growth in vivo. DK419 (1 mg/kg) inhibits CRC240 PDX tumor growth in mice via oral administration once a day.

DK419 is a potent and orally active Wnt/β-catenin inhibitor, with great potency in the treatment of colorectal cancer.

1. Wang J, et al. Bioorg Med Chem. 2018 Nov 1;26(20):5435-5442.