Novel small molecules downregulate CDK1 expression and inhibit Wnt/β-catenin signaling in cutaneous squamous cell carcinoma by targeting its distinct tumor-specific cellular landscape.

The Wnt/β-catenin pathway is an attractive target for drug development in various diseases; however, efforts to target it have been limited due to its concerning role in cancer. We previously developed KY19382 and KY19334, small molecules that inhibit the cytosolic function of CXXC-type zinc finger protein 5 (CXXC5), as safe therapeutic agents to restore the suppressed Wnt/β-catenin signaling in several intractable diseases, but the effects of these small molecules on cancer have not been determined. Here, we found that KY19382 and KY19334 inhibited the manifestation of malignant phenotype by inhibiting the Wnt/β-catenin signaling of human cutaneous squamous cell carcinoma (cSCC) cells, which was associated with suppression of cyclin-dependent kinase 1 (CDK1) expression. The induced expression of CDK1 and subsequent Wnt/β-catenin pathway activation were observed in human cSCC patient samples compared with normal samples, and the roles of CDK1 in cellular transformation and Wnt/β-catenin pathway activation in human cSCC cells were validated by CDK1 knockdown. Moreover, the two small molecules attenuated two-stage mouse skin carcinogenesis. Overall, KY19382 and KY19334 could be used as agents to treat cSCC and other types of cancer caused by CDK1 overexpression, as well as diseases caused by cytoplasmic accumulation of CXXC5.