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

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

  • J Exp Clin Cancer Res. 2025 Oct 17;44(1):292. doi: 10.1186/s13046-025-03538-w.
Mohammed Moustapha Anwar 1,  Salvador Meseguer 1,  Néstor García-Rodríguez 2,  Ewa Krupinska 3,  Céleste Sele 3,  Aida Rodríguez-Jiménez 1,  Suraj Verma 4,  Samna Sagadevan 5,  Javier Ramon 6 7,  Ramon Martí 6 7,  Annalisa Occhipinti 4 8,  Claudio Angione 4 8,  Paloma Ordóñez-Morán 5,  Wolfgang Knecht 3 9,  Pablo Huertas 2,  M Angeles Juanes 10
Affiliations

Affiliations

  • 1 Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Lab, Department of Cancer, Centro de Investigación Príncipe Felipe (CIPF), Valencia, 46012, Spain.
  • 2 Department of Genome Biology, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla-CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Seville, Spain.
  • 3 Department of Biology & Lund Protein Production Platform & Protein Production Sweden, Lund University, Sölvegatan 35, Lund, 22362, Sweden.
  • 4 School of Computing, Engineering and Digital Technologies, Teesside University, Middlesborough, UK.
  • 5 Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
  • 6 Research Group On Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.
  • 7 Biomedical Network Research Centre On Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.
  • 8 National Horizons Centre, Teesside University, Darlington, UK.
  • 9 Science for Life Laboratory, Department of Biology & Lund Protein Production Platform & Protein Production Sweden, Lund University, Sölvegatan 35, Lund, 22362, Sweden.
  • 10 Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Lab, Department of Cancer, Centro de Investigación Príncipe Felipe (CIPF), Valencia, 46012, Spain. majuanes@cipf.es.
PMID: 41107985 DOI: 10.1186/s13046-025-03538-w
Abstract

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.

Keywords

Cancer; DHODH; NK-A 17E-233I; Pyrimidine de novo synthesis.

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