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<p>Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural&#xa0;substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.</p> Graphical Abstract <p></p>

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NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月17日

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  • Mohammed Moustapha Anwar,
  • Salvador Meseguer,
  • Néstor García-Rodríguez,
  • Ewa Krupinska,
  • Céleste Sele,
  • Aida Rodríguez-Jiménez,
  • Suraj Verma,
  • Samna Sagadevan,
  • Javier Ramon,
  • Ramon Martí,
  • Annalisa Occhipinti,
  • Claudio Angione,
  • Paloma Ordóñez-Morán,
  • Wolfgang Knecht,
  • Pablo Huertas,
  • M. Angeles Juanes

摘要

Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.

Graphical Abstract