ArticleCurrent issues in molecular biology2025
Selective Dual Inhibition of TNKS1 and CDK8 by TCS9725 Attenuates STAT1/β-Catenin/TGFβ1 Signaling in Renal Cancer.
Article in Current issues in molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundTankyrase (TNKS1) regulates the WNT/β-catenin pathway, while CDK8 is a transcriptional regulator overexpressed in renal cell carcinoma (RCC). This study aims to identify novel dual inhibitors of tankyrase and Cyclin-dependent kinase 8 (CDK8), utilizing bioinformatics and in vitro methods and to assess their efficiency in renal cancer cells.
methodsTo identify leads, the ChemBridge library was screening using high-throughput virtual screening (HTVS), which was followed by protein-ligand interaction analysis, Molecular Dynamics (MD) simulation, and Gibbs binding free energy estimation. A-498, Caki-1, and HK-2 cells were employed to validate in vitro efficacy.
resultsTCS9725 was discovered by HTVS with binding affinities of -8.1 kcal/mol and -8.2 kcal/mol for TNKS1 and CDK8, respectively. TCS9725 had robust binding interactions with root mean square deviation values of 0.00 nm. The ΔG binding estimate was -27.45 for TNKS1 and -27.88 for CDK8, respectively. ADME predictions favored specific small-molecule inhibition profiles. TCS9725 reduced TNKS1 and CDK8 activities with IC50s of 243 nM and 403.6 nM, respectively. The compound efficiently inhibited the growth of A-498 and Caki-1 cells with GI50 values of 385.9 nM and 243.6 nM, respectively, with high selectivity compared to the non-cancerous kidney cells. TCS9725 decreased STAT1 and β-catenin positivity in A-498 and Caki-1 cells. The compound induced apoptosis and reduced TGFβ-stimulated trans-endothelial migration and p-smad2/3 signaling in both RCC cells.
conclusionsThis work provides valuable insights into the therapeutic potential of TCS9725, a dual inhibitor of TNKS1 and CDK8. Further developments of this molecule could lead to new and effective treatments for this devastating disease.
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