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

Anwar, Mohammed Moustapha LU orcid ; Meseguer, Salvador ; García-Rodríguez, Néstor ; Krupinska, Ewa LU ; Sele, Céleste LU ; Rodríguez-Jiménez, Aida ; Verma, Suraj ; Sagadevan, Samna ; Ramon, Javier and Martí, Ramon , et al. (2025) In Journal of Experimental & Clinical Cancer Research 44.
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Experimental & Clinical Cancer Research
volume
44
article number
292
publisher
BioMed Central (BMC)
external identifiers
  • pmid:41107985
ISSN
1756-9966
DOI
10.1186/s13046-025-03538-w
language
English
LU publication?
yes
id
907b2fe8-10b1-4196-83d7-e54109bcb348
date added to LUP
2025-10-18 15:40:57
date last changed
2025-10-25 03:44:12
@article{907b2fe8-10b1-4196-83d7-e54109bcb348,
  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.}},
  author       = {{Anwar, Mohammed Moustapha and Meseguer, Salvador and García-Rodríguez, Néstor and Krupinska, Ewa and Sele, Céleste and Rodríguez-Jiménez, Aida and Verma, Suraj and Sagadevan, Samna and Ramon, Javier and Martí, Ramon and Occhipinti, Annalisa and Angione, Claudio and Ordóñez-Morán, Paloma and Knecht, Wolfgang and Huertas, Pablo and Juanes, M. Angeles}},
  issn         = {{1756-9966}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Experimental & Clinical Cancer Research}},
  title        = {{NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy}},
  url          = {{http://dx.doi.org/10.1186/s13046-025-03538-w}},
  doi          = {{10.1186/s13046-025-03538-w}},
  volume       = {{44}},
  year         = {{2025}},
}