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Peer-reviewedCC BY 4.0Molecules

Tumor-Dependent Cytotoxicity of Novel Benzodiazepinones Across Cancers with Distinct IAP-Associated Aggressiveness

  • Michele Fiore1
  • Dario Lunaccio2
  • Elisa Fagnani3
  • Paolo Cocomazzi3
  • Francesco Bonì3
  • Bruno Tasso4
  • Annalisa Salis2
  • Enrico Millo2
  • Federica Cossu3
4 affiliations
  1. 1Institute of Biophysics-National Research Council (IBF-CNR) Genoa Unit, via De Marini, 6, 16149 Genoa, Italy
  2. 2Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy
  3. 3Institute of Biophysics-National Research Council (IBF-CNR) Milan Unit, Via Corti 12, 20133 Milano, Italy
  4. 4Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
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Abstract

Inhibitor of Apoptosis Proteins (IAPs) are key regulators of tumor progression, invasiveness, and chemoresistance, and their contribution varies across different tumor types. Here, we evaluated an expanded library of benzodiazepinone derivatives in invasive and chemoresistant human cancer cell lines (MDA-MB-231, BT-549, NCI-H1299, and PC-3), in which IAP-dependent signaling has been implicated to different extents. These compounds were developed from a parental benzodiazepinone previously shown to bind IAPs in vitro using isolated proteins and to target IAPs in MDA-MB-231 cells. The expanded library retained cytotoxic activity beyond MDA-MB-231 cells, extending to BT-549 and NCI-H1299, whereas limited effect was observed in PC-3 cells. Tumor Necrosis Factor (TNFα) co-treatment further enhanced the cytotoxic activity of selected derivatives, although the magnitude of this effect differed among cell lines, suggesting a differential contribution of TNFα/NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling, potentially involving IAP regulated pathway. Overall, these findings expand the biological profile of this benzodiazepinone scaffold and support its further investigation as a promising lead for the development of therapies against aggressive and chemoresistant cancers.

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Cite

BibTeXRIS
BibTeX
@article{fiore2026tumordependent,
  title = {{Tumor-Dependent Cytotoxicity of Novel Benzodiazepinones Across Cancers with Distinct IAP-Associated Aggressiveness}},
  author = {Michele Fiore and Dario Lunaccio and Elisa Fagnani and Paolo Cocomazzi and Francesco Bonì and Bruno Tasso and Annalisa Salis and Enrico Millo and Federica Cossu},
  journal = {Molecules},
  year = {2026},
  month = nov,
  doi = {10.3390/molecules31214016},
  url = {https://www.mdpi.com/1420-3049/31/21/4016},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tumor-Dependent Cytotoxicity of Novel Benzodiazepinones Across Cancers with Distinct IAP-Associated Aggressiveness
AU  - Michele Fiore
AU  - Dario Lunaccio
AU  - Elisa Fagnani
AU  - Paolo Cocomazzi
AU  - Francesco Bonì
AU  - Bruno Tasso
AU  - Annalisa Salis
AU  - Enrico Millo
AU  - Federica Cossu
PY  - 2026
DA  - 2026/11/07
JO  - Molecules
DO  - 10.3390/molecules31214016
UR  - https://www.mdpi.com/1420-3049/31/21/4016
AB  - Inhibitor of Apoptosis Proteins (IAPs) are key regulators of tumor progression, invasiveness, and chemoresistance, and their contribution varies across different tumor types. Here, we evaluated an expanded library of benzodiazepinone derivatives in invasive and chemoresistant human cancer cell lines (MDA-MB-231, BT-549, NCI-H1299, and PC-3), in which IAP-dependent signaling has been implicated to different extents. These compounds were developed from a parental benzodiazepinone previously shown to bind IAPs in vitro using isolated proteins and to target IAPs in MDA-MB-231 cells. The expanded library retained cytotoxic activity beyond MDA-MB-231 cells, extending to BT-549 and NCI-H1299, whereas limited effect was observed in PC-3 cells. Tumor Necrosis Factor (TNFα) co-treatment further enhanced the cytotoxic activity of selected derivatives, although the magnitude of this effect differed among cell lines, suggesting a differential contribution of TNFα/NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling, potentially involving IAP regulated pathway. Overall, these findings expand the biological profile of this benzodiazepinone scaffold and support its further investigation as a promising lead for the development of therapies against aggressive and chemoresistant cancers.
SN  - 1420-3049
ER  -