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Novel small molecules downregulate CDK1 expression and inhibit Wnt/β-catenin signaling in cutaneous squamous cell

Soung-Hoon Lee1, Min-Jeong Kang2, Mi Ryung Roh3

  • 1CK Regeon Inc., Yonsei Engineering Research Park, Yonsei-ro 50, Seodaemoon-gu, Seoul, South Korea. greateondal84@yuhs.ac.

Experimental & Molecular Medicine
|August 31, 2025
PubMed

Insights

New small molecules, KY19382 and KY19334, inhibit Wnt/β-catenin signaling and suppress cancer cell growth. These agents show promise for treating cutaneous squamous cell carcinoma (cSCC) and other cancers driven by CDK1 overexpression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • The Wnt/β-catenin pathway is crucial in development but implicated in cancer.
  • Targeting Wnt/β-catenin is challenging due to its dual role in disease and cancer.
  • CXXC-type zinc finger protein 5 (CXXC5) regulates Wnt/β-catenin signaling.

Purpose of the Study:

  • To investigate the anti-cancer effects of CXXC5 inhibitors KY19382 and KY19334.
  • To determine the role of these inhibitors in cutaneous squamous cell carcinoma (cSCC).
  • To explore the potential of these molecules as therapeutic agents for specific cancers.

Main Methods:

  • Treatment of human cutaneous squamous cell carcinoma (cSCC) cells with KY19382 and KY19334.
  • Analysis of Wnt/β-catenin signaling pathway components and cyclin-dependent kinase 1 (CDK1) expression.
  • Validation of CDK1's role via knockdown experiments.
  • Assessment of the small molecules' efficacy in a two-stage mouse skin carcinogenesis model.

Main Results:

  • KY19382 and KY19334 inhibited malignant phenotype in cSCC cells by suppressing Wnt/β-catenin signaling.
  • Inhibition of Wnt/β-catenin signaling correlated with reduced cyclin-dependent kinase 1 (CDK1) expression.
  • Elevated CDK1 expression and Wnt/β-catenin pathway activation were observed in human cSCC samples.
  • The small molecules demonstrated efficacy in attenuating mouse skin carcinogenesis.

Conclusions:

  • KY19382 and KY19334 effectively inhibit Wnt/β-catenin signaling and suppress cSCC progression.
  • These compounds represent potential therapeutic agents for cSCC and other cancers associated with CDK1 overexpression.
  • The findings support the use of these inhibitors for diseases linked to CXXC5 cytoplasmic accumulation.

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