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<p>This study provides insight into therapy for lung cancer, establishing <i>p-C</i>resol (<i>p-C)</i> as an inhibitor of Pyruvate Dehydrogenase Kinase 3 (PDK3). PDK3 is critical in cancer metabolism by regulating the pyruvate dehydrogenase complex, shifting cellular energy production towards glycolysis, and promoting tumor growth and survival under hypoxic conditions. In this study, we have used computational and experimental approaches. Molecular docking reveals that <i>p-C</i> occupies PDK3’s binding pocket and forms interactions with key residues, especially Asp 287. Molecular dynamic simulation (MD) studies showed that <i>p-C</i> induced minimum alterations in PDK3, suggesting the structural stability of the PDK3-<i>p-C</i> complex. A fluorescence-based binding study demonstrated the binding of <i>p-C</i> to PDK3 with a binding constant of 3.8 × 10<sup>8</sup> M<sup>−1</sup>, indicating excellent binding affinity. Cell-based enzyme assay revealed significant inhibition of PDK3 by <i>p-C</i>, establishing it as a PDK3 inhibitor. Moreover, cellular assays also demonstrated significant inhibition of PDK3 activity and tumor progression. This study provides a promising therapeutic avenue for improving lung cancer treatment outcomes by targeting PDK3.&#xa0;</p>

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Targeting cancer metabolism through p-cresol mediated Inhibition of pyruvate dehydrogenase kinase 3 in lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • Akram Ashames,
  • Saleha Anwar,
  • Md Nayab Sulaimani,
  • Pinky,
  • Mohd Shahnawaz Khan,
  • Moyad Shahwan,
  • Suhel Parvez,
  • Md. Imtaiyaz Hassan,
  • Khuzin Dinislam,
  • Anas Shamsi

摘要

This study provides insight into therapy for lung cancer, establishing p-Cresol (p-C) as an inhibitor of Pyruvate Dehydrogenase Kinase 3 (PDK3). PDK3 is critical in cancer metabolism by regulating the pyruvate dehydrogenase complex, shifting cellular energy production towards glycolysis, and promoting tumor growth and survival under hypoxic conditions. In this study, we have used computational and experimental approaches. Molecular docking reveals that p-C occupies PDK3’s binding pocket and forms interactions with key residues, especially Asp 287. Molecular dynamic simulation (MD) studies showed that p-C induced minimum alterations in PDK3, suggesting the structural stability of the PDK3-p-C complex. A fluorescence-based binding study demonstrated the binding of p-C to PDK3 with a binding constant of 3.8 × 108 M−1, indicating excellent binding affinity. Cell-based enzyme assay revealed significant inhibition of PDK3 by p-C, establishing it as a PDK3 inhibitor. Moreover, cellular assays also demonstrated significant inhibition of PDK3 activity and tumor progression. This study provides a promising therapeutic avenue for improving lung cancer treatment outcomes by targeting PDK3.