Lee Soung-Hoon, Kang Min-Jeong, Roh Mi Ryung, Choi Kang-Yell
CK Regeon Inc., Yonsei Engineering Research Park, Yonsei-ro 50, Seodaemoon-gu, Seoul, South Korea.
Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, College of Medicine; Yonsei University, Seoul, South Korea.
Exp Mol Med. 2025 Sep 1. doi: 10.1038/s12276-025-01532-y.
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.
Wnt/β-连环蛋白信号通路是各类疾病药物研发中一个颇具吸引力的靶点；然而，由于其在癌症中的不良作用，针对该通路的研究进展有限。我们之前研发了KY19382和KY19334这两种小分子化合物，它们可抑制CXXC型锌指蛋白5（CXXC5）的胞质功能，作为安全的治疗药物用于恢复几种难治性疾病中被抑制的Wnt/β-连环蛋白信号传导，但尚未确定这些小分子化合物对癌症的影响。在此，我们发现KY19382和KY19334通过抑制人皮肤鳞状细胞癌（cSCC）细胞的Wnt/β-连环蛋白信号传导来抑制恶性表型的表现，这与细胞周期蛋白依赖性激酶1（CDK1）表达的抑制有关。与正常样本相比，在人cSCC患者样本中观察到了CDK1的诱导表达及随后的Wnt/β-连环蛋白信号通路激活，并且通过敲低CDK1验证了其在人cSCC细胞的细胞转化和Wnt/β-连环蛋白信号通路激活中的作用。此外，这两种小分子化合物减弱了两阶段小鼠皮肤癌发生。总体而言，KY19382和KY19334可作为治疗cSCC及其他由CDK1过表达引起的癌症类型以及由CXXC5胞质积累引起的疾病的药物。
