New Class of Benzodiazepinone Derivatives as Pro-Death Agents Targeting BIR Domains in Cancer Cells

Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF...

Full description

Saved in:

Bibliographic Details
Published in:	Molecules (Basel, Switzerland) Switzerland), 2023-01, Vol.28 (1), p.446
Main Authors:	Fiore, Michele, Mosconi, Michele, Bonì, Francesco, Parodi, Alice, Salis, Annalisa, Tasso, Bruno, Mastrangelo, Eloise, Millo, Enrico, Cossu, Federica
Format:	Article
Language:	eng
Subjects:	Adenocarcinoma Antagonists Antineoplastic Agents - pharmacology Apoptosis baculoviral IAP repeat (BIR) benzodiazepinone Benzodiazepinones - pharmacology Binding Cancer Care and treatment Chemoresistance Cytotoxicity Deregulation DIABLO protein Domains Fluorescence GABA IAP protein inhibitor of apoptosis protein (IAP) Inhibitor of Apoptosis Proteins - metabolism Instrument industry Intracellular Signaling Peptides and Proteins - metabolism MDA-MB-231 Medical prognosis Mitochondrial Proteins - metabolism Neoplasms NF-kappa B - metabolism NF-κB (nuclear factor kappa light chain enhancer of activated B cells) NF-κB protein Protein Binding Proteins Tumor necrosis factor Tumor necrosis factor-TNF Tumors virtual docking XIAP protein
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF-κB pathway modulator in MDA-MB-231 adenocarcinoma cancer cells after virtual screening of the Chembridge library against the Baculoviral IAP Repeat 1 (BIR1) domain of cIAP2 and XIAP. An improved cytotoxic effect is observed when FC2 is combined with Smac-mimetics or with the cytokine Tumor Necrosis Factor (TNF). Here, we propose a library of 22 derivatives of FC2, whose scaffold was rationally modified starting from the position identified as R . The cytotoxic effect of FC2 derivatives was evaluated in MDA-MB-231 and binding to the cIAP2- and XIAP-BIR1 domains was assessed in fluorescence-based techniques and virtual docking. Among 22 derivatives, and display improved efficacy/potency in MDA-MB-231 cells and low micromolar binding affinity vs the target proteins. Two additional candidates ( and ) display promising cytotoxic effects in combination with TNF, suggesting the connection between this class of molecules and the NF-κB pathway. These results provide the rationale for further FC2 modifications and the design of novel IAP-targeting candidates supporting known therapies.
ISSN:	1420-3049 1420-3049