Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked i...

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Autores principales:	Annalaura Brai, Valentina Riva, Letizia Clementi, Lucia Falsitta, Claudio Zamperini, Virginia Sinigiani, Claudio Festuccia, Samantha Sabetta, Davide Aiello, Camilla Roselli, Anna Garbelli, Claudia Immacolata Trivisani, Laura Maccari, Francesca Bugli, Maurizio Sanguinetti, Pierpaolo Calandro, Mario Chiariello, Paola Quaranta, Lorenzo Botta, Adriano Angelucci, Giovanni Maga, Maurizio Botta
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DDX3X glioblastoma anticancer xenograft helicase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/bfbd4134848143b985f3e9e04faac2e5
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spelling	oai:doaj.org-article:bfbd4134848143b985f3e9e04faac2e52021-11-11T15:35:30ZTargeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models10.3390/cancers132155692072-6694https://doaj.org/article/bfbd4134848143b985f3e9e04faac2e52021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5569https://doaj.org/toc/2072-6694DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.Annalaura BraiValentina RivaLetizia ClementiLucia FalsittaClaudio ZamperiniVirginia SinigianiClaudio FestucciaSamantha SabettaDavide AielloCamilla RoselliAnna GarbelliClaudia Immacolata TrivisaniLaura MaccariFrancesca BugliMaurizio SanguinettiPierpaolo CalandroMario ChiarielloPaola QuarantaLorenzo BottaAdriano AngelucciGiovanni MagaMaurizio BottaMDPI AGarticleDDX3Xglioblastomaanticancerxenografthelicase inhibitorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5569, p 5569 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DDX3X glioblastoma anticancer xenograft helicase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	DDX3X glioblastoma anticancer xenograft helicase inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Annalaura Brai Valentina Riva Letizia Clementi Lucia Falsitta Claudio Zamperini Virginia Sinigiani Claudio Festuccia Samantha Sabetta Davide Aiello Camilla Roselli Anna Garbelli Claudia Immacolata Trivisani Laura Maccari Francesca Bugli Maurizio Sanguinetti Pierpaolo Calandro Mario Chiariello Paola Quaranta Lorenzo Botta Adriano Angelucci Giovanni Maga Maurizio Botta Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
description	DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.
format	article
author	Annalaura Brai Valentina Riva Letizia Clementi Lucia Falsitta Claudio Zamperini Virginia Sinigiani Claudio Festuccia Samantha Sabetta Davide Aiello Camilla Roselli Anna Garbelli Claudia Immacolata Trivisani Laura Maccari Francesca Bugli Maurizio Sanguinetti Pierpaolo Calandro Mario Chiariello Paola Quaranta Lorenzo Botta Adriano Angelucci Giovanni Maga Maurizio Botta
author_facet	Annalaura Brai Valentina Riva Letizia Clementi Lucia Falsitta Claudio Zamperini Virginia Sinigiani Claudio Festuccia Samantha Sabetta Davide Aiello Camilla Roselli Anna Garbelli Claudia Immacolata Trivisani Laura Maccari Francesca Bugli Maurizio Sanguinetti Pierpaolo Calandro Mario Chiariello Paola Quaranta Lorenzo Botta Adriano Angelucci Giovanni Maga Maurizio Botta
author_sort	Annalaura Brai
title	Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
title_short	Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
title_full	Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
title_fullStr	Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
title_full_unstemmed	Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models
title_sort	targeting ddx3x helicase activity with ba103 shows promising therapeutic effects in preclinical glioblastoma models
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bfbd4134848143b985f3e9e04faac2e5
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Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models

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