2. Academic Validation
  3. Discovery of KDX1381, a Bivalent CK2α Inhibitor for the Treatment of Solid Tumors as a Single Agent or in Combination

Discovery of KDX1381, a Bivalent CK2α Inhibitor for the Treatment of Solid Tumors as a Single Agent or in Combination

  • J Med Chem. 2025 Jun 26;68(12):12819-12844. doi: 10.1021/acs.jmedchem.5c00695.
Léna Marlhoux 1 2,  Alexandre Arnaud 1,  Céline Hervieu 1,  Gabriela Makulyte 1,  Charlotte Martinasso 3,  Angélique Mularoni 3,  Jean-Guy Delcros 3,  Isabelle Krimm 3,  Hector Hernandez-Vargas 4,  Gabriel Ichim 2,  Olivier Meurette 2,  David Neves 1,  Alexandre Bancet 1
Affiliations

Affiliations

  • 1 Kairos Discovery, 36 rue Jeanne d'Arc, Lyon 69003, France.
  • 2 Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Institut Convergence Plascan, Team ≪ Cancer Cell Death ≫, Lyon 69373, France.
  • 3 Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Institut Convergence Plascan, Team ≪ Small Molecules for Biological Targets ≫, Lyon 69373, France.
  • 4 Genomics Consulting, 36B rue de la Batterie, Bron 69500, France.
PMID: 40493957 DOI: 10.1021/acs.jmedchem.5c00695
Abstract

Casein Kinase 2 (CK2) has emerged as a promising therapeutic target across a broad spectrum of malignancies, including pediatric and orphan cancers. The identification of a ligandable allosteric αD pocket on the CK2α subunit has enabled the development of bivalent inhibitors, which bind simultaneously to both the adenosine triphosphate (ATP) site and the allosteric pocket. Here, we report the discovery and pharmacological characterization of KDX1381, a structure-guided bivalent CK2α inhibitor with low-nanomolar potency and high selectivity, confirmed by cocrystal structures. In mice, KDX1381 suppressed CK2-driven tumor growth as a monotherapy and enhanced therapeutic efficacy when combined with vascular endothelial growth factor receptor (VEGFR) inhibitors or DNA-damaging agents in hepatocellular carcinoma and glioma models. These findings support bivalent CK2α inhibition as a differentiated therapeutic strategy with broad applicability in CK2-dependent cancers.

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