3-nitropyridine analogues as novel microtubule-targeting agents
Microtubule-targeting agents are an important class of anti-cancer drugs; their full potential is however not realized because of significant myelotoxicity and neurotoxicity. We here report 3-nitropyridine analogues as a novel group of microtubule-targeting agents with potent anti-cancer effects against a broad range of cancer types. We show that these 3-nitropyridines induce cell cycle arrest in the G2-M phase and inhibit tubulin polymerization by interacting with tubulin. Determination of the tubulin-4AZA2996 structure by X-ray crystallography demonstrated that this class of compounds binds to the colchicine-site of tubulin. Furthermore, the anti-cancer effect was demonstrated both in vitro and in vivo in a murine heterotopic xenograft model of colon cancer. When administered intravenously, 4AZA2891 effectively inhibited cancer growth. Whereas 3-nitropyridine compounds do not induce myelotoxicity at pharmacological doses, the neurotoxicity associated with microtubule-targeting agents is still present.
Authors
- Michel Olivier Steinmetz (ORCID: https://orcid.org/0000-0001-6157-3687)
- Ling‐Jie Gao (ORCID: https://orcid.org/0000-0001-8889-3621)
- Thierry Louat (ORCID: https://orcid.org/0000-0002-3920-2916)
- Ben Sprangers (ORCID: https://orcid.org/0000-0003-1314-9675)
- Piet A. Herdewijn (ORCID: https://orcid.org/0000-0003-3589-8503)
- Dorothée Bardiot
- Steven De Jonghe (ORCID: https://orcid.org/0000-0002-3872-6558)
- Andrea Enrico Prota (ORCID: https://orcid.org/0000-0003-0875-5339)
- Jean Herman (ORCID: https://orcid.org/0000-0002-6774-1685)
- Thomas Vercruysse (ORCID: https://orcid.org/0000-0002-8649-777X)
- Leentje Persoons (ORCID: https://orcid.org/0000-0002-7898-0868)
- Natacha Gaillard (ORCID: https://orcid.org/0000-0002-1129-1291)
- Dirk Daelemans (ORCID: https://orcid.org/0000-0001-7092-1153)
- Els Vanstreels (ORCID: https://orcid.org/0000-0002-7814-8035)
- Mark Waer
- Tinne Daems
Institutions
- University of Basel (CH)
- Rega Institute for Medical Research (BE)
- Paul Scherrer Institute (CH)
- KU Leuven (BE)
Publication Details
- Journal
- PLoS ONE
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1371/journal.pone.0307153
- Citations
- 2
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.65
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Paul Scherrer Institut
- Vlaamse regering