Casein Kinase 1 and CK2 as Therapeutic Targets in Cancer: Molecular Pharmacology, Toxicological Considerations, and Clinical Progress.
Casein kinase 1 (CK1) and casein kinase 2 (CK2) are highly conserved serine/threonine protein kinases that regulate multiple oncogenic signaling pathways involved in cancer progression, metastasis, and therapeutic resistance. Overexpression or dysregulation of CK1 and CK2 has been shown to contribute to the development and resistance of cancer to anticancer therapies. This review summarizes the molecular functions of CK1 and CK2 in cancer biology and evaluates the therapeutic potential, pharmacological development, and clinical progress of CK-targeted inhibitors. A structured literature search was performed using PubMed, Scopus, and Web of Science databases to identify studies published between 2000 and 2026 related to CK1/CK2 signaling, pharmacological inhibitors, toxicology, and clinical development. CK1 and CK2 are involved in the regulation of various oncogenic signaling pathways, including the Wnt/β-catenin, p53, nuclear factor kappa B, and phosphatidylinositol-3-kinase/protein kinase B signaling pathways, as well as genomic integrity pathways. Dysregulation of these kinases leads to the survival, proliferation, and resistance of cancer cells to anticancer therapies. Several CK inhibitors, including CX-4945 (Silmitasertib), CIGB- 300, IC261, D4476, SR-3029, and BTX-A51, have shown promising anticancer activity in various cancer models. Novel dual-therapy approaches targeting CK1/CK2-regulated pathways have further improved the therapeutic specificity and efficacy. CK-targeting therapies are an exciting approach and hold great promise for selectively targeting cancer-causing signaling pathways and advancing cancer precision medicine.