Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway

Inhibitors of apoptosis proteins (IAPs) are validated onco-targets, as their overexpression correlates with cancer onset, progression, diffusion and chemoresistance. IAPs regulate cell death survival pathways, inflammation, and immunity. Targeting IAPs, by impairing their protein–protein interaction...

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Autores principales:	Federica Cossu, Simone Camelliti, Daniele Lecis, Luca Sorrentino, Maria Teresa Majorini, Mario Milani, Eloise Mastrangelo
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Virtual screening Inhibitor of apoptosis proteins Baculoviral IAP repeat IAP-antagonist NF-kB Drug discovery Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/c86117b4d2eb46419e5f2244e91de453
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spelling	oai:doaj.org-article:c86117b4d2eb46419e5f2244e91de4532021-12-04T04:33:34ZStructure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway2001-037010.1016/j.csbj.2021.11.034https://doaj.org/article/c86117b4d2eb46419e5f2244e91de4532021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2001037021004992https://doaj.org/toc/2001-0370Inhibitors of apoptosis proteins (IAPs) are validated onco-targets, as their overexpression correlates with cancer onset, progression, diffusion and chemoresistance. IAPs regulate cell death survival pathways, inflammation, and immunity. Targeting IAPs, by impairing their protein–protein interaction surfaces, can affect events occurring at different stages of cancer development.To this purpose, we employed a rational virtual screening approach to identify compounds predicted to interfere with the assembly of pro-survival macromolecular complexes. One of the candidates, FC2, was shown to bind in vitro the BIR1 domains of both XIAP and cIAP2. Moreover, we demonstrated that FC2 can induce cancer cell death as a single agent and, more potently, in combination with the Smac-mimetic SM83 or with the cytokine TNF. FC2 determined a prolonged activation of the NF-κB pathway, accompanied to a stabilization of XIAP-TAB1 complex. This candidate molecule represents a valuable lead compound for the development of a new class of IAP-antagonists for cancer treatment.Federica CossuSimone CamellitiDaniele LecisLuca SorrentinoMaria Teresa MajoriniMario MilaniEloise MastrangeloElsevierarticleVirtual screeningInhibitor of apoptosis proteinsBaculoviral IAP repeatIAP-antagonistNF-kBDrug discoveryBiotechnologyTP248.13-248.65ENComputational and Structural Biotechnology Journal, Vol 19, Iss , Pp 6366-6374 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Virtual screening Inhibitor of apoptosis proteins Baculoviral IAP repeat IAP-antagonist NF-kB Drug discovery Biotechnology TP248.13-248.65
spellingShingle	Virtual screening Inhibitor of apoptosis proteins Baculoviral IAP repeat IAP-antagonist NF-kB Drug discovery Biotechnology TP248.13-248.65 Federica Cossu Simone Camelliti Daniele Lecis Luca Sorrentino Maria Teresa Majorini Mario Milani Eloise Mastrangelo Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
description	Inhibitors of apoptosis proteins (IAPs) are validated onco-targets, as their overexpression correlates with cancer onset, progression, diffusion and chemoresistance. IAPs regulate cell death survival pathways, inflammation, and immunity. Targeting IAPs, by impairing their protein–protein interaction surfaces, can affect events occurring at different stages of cancer development.To this purpose, we employed a rational virtual screening approach to identify compounds predicted to interfere with the assembly of pro-survival macromolecular complexes. One of the candidates, FC2, was shown to bind in vitro the BIR1 domains of both XIAP and cIAP2. Moreover, we demonstrated that FC2 can induce cancer cell death as a single agent and, more potently, in combination with the Smac-mimetic SM83 or with the cytokine TNF. FC2 determined a prolonged activation of the NF-κB pathway, accompanied to a stabilization of XIAP-TAB1 complex. This candidate molecule represents a valuable lead compound for the development of a new class of IAP-antagonists for cancer treatment.
format	article
author	Federica Cossu Simone Camelliti Daniele Lecis Luca Sorrentino Maria Teresa Majorini Mario Milani Eloise Mastrangelo
author_facet	Federica Cossu Simone Camelliti Daniele Lecis Luca Sorrentino Maria Teresa Majorini Mario Milani Eloise Mastrangelo
author_sort	Federica Cossu
title	Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
title_short	Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
title_full	Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
title_fullStr	Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
title_full_unstemmed	Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway
title_sort	structure-based identification of a new iap-targeting compound that induces cancer cell death inducing nf-κb pathway
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c86117b4d2eb46419e5f2244e91de453
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Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway

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