{"entity": "publication", "iuid": "772b4d10179e46638d61b40f1f4419f0", "timestamp": "2026-10-01T11:59:46.432Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/772b4d10179e46638d61b40f1f4419f0.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/772b4d10179e46638d61b40f1f4419f0"}}, "title": "NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.", "authors": [{"family": "Anwar", "given": "Mohammed Moustapha", "initials": "MM"}, {"family": "Meseguer", "given": "Salvador", "initials": "S"}, {"family": "Garc\u00eda-Rodr\u00edguez", "given": "N\u00e9stor", "initials": "N"}, {"family": "Krupinska", "given": "Ewa", "initials": "E"}, {"family": "Sele", "given": "C\u00e9leste", "initials": "C"}, {"family": "Rodr\u00edguez-Jim\u00e9nez", "given": "Aida", "initials": "A"}, {"family": "Verma", "given": "Suraj", "initials": "S"}, {"family": "Sagadevan", "given": "Samna", "initials": "S"}, {"family": "Ramon", "given": "Javier", "initials": "J"}, {"family": "Mart\u00ed", "given": "Ramon", "initials": "R"}, {"family": "Occhipinti", "given": "Annalisa", "initials": "A"}, {"family": "Angione", "given": "Claudio", "initials": "C"}, {"family": "Ord\u00f3\u00f1ez-Mor\u00e1n", "given": "Paloma", "initials": "P"}, {"family": "Knecht", "given": "Wolfgang", "initials": "W"}, {"family": "Huertas", "given": "Pablo", "initials": "P"}, {"family": "Juanes", "given": "M Angeles", "initials": "MA"}], "type": "journal article", "published": "2025-10-17", "journal": {"title": "J. Exp. Clin. Cancer Res.", "issn": "1756-9966", "volume": "44", "issue": "1", "pages": "292", "issn-l": "1756-9966"}, "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.", "doi": "10.1186/s13046-025-03538-w", "pmid": "41107985", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12534982"}, {"db": "pii", "key": "10.1186/s13046-025-03538-w"}], "notes": [], "created": "2026-10-01T08:27:07.591Z", "modified": "2026-10-01T08:27:07.618Z"}