CNR ExploRA

Articolo in rivista, 2021, ENG, 10.3390/cancers13215569

Targeting ddx3x helicase activity with ba103 shows promising therapeutic effects in preclinical glioblastoma models

Brai A, Riva V, Clementi L, Falsitta L, Zamperini C, Sinigiani V, Festuccia C, Sabetta S, Aiello D, Roselli C, Garbelli A, Trivisani CI, Maccari L, Bugli F, Sanguinetti M, Calandro P, Chiariello M, Quaranta P, Botta L, Angelucci A, Maga G, Botta M.

Department of Biotechnology, Chemistry & Pharmacy, University of Siena, Siena, I-53100, Department of Biotechnology, Chemistry & Pharmacy, University of Siena, I-53100, Siena, Italy, , Italy; Istituto di Genetica Molecolare Luigi Luca Cavalli Sforza, IGM-CNR, Via Abbiategrasso 207, Pavia, I-27100, Istituto di Genetica Molecolare Luigi Luca Cavalli Sforza, IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy, , Italy; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, I-67100, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, I-67100, L'Aquila, Italy, , Italy; Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, 00168, Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168, Rome, Italy, , Italy; Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy, , Italy; Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, Siena, 53100, Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100, Siena, Italy, , , , Italy; Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, Siena, 53100, Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100, Siena, Italy, , , , Italy; Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, Siena, 53100, Consiglio Nazionale delle Ricerche (CNR) and Core Research Laboratory (CRL), Istituto di Fisiologia Clinica (IFC), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100, Siena, Italy, , , , Italy; Department of Translational Research, University of Pisa, Pisa, I-56127, Department of Translational Research, University of Pisa, I-56127, Pisa, Italy, , Italy; Department of Ecological and Biological Sciences, University of Tuscia, Via S.C. De Lellis s.n.c., Viterbo, I-01100, Department of Ecological and Biological Sciences, University of Tuscia, Via S.C. De Lellis s.n.c., I-01100, Viterbo, Italy, , Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA, 19122, Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, BioLife Science Building, Suite 333, Temple University, 1900 N 12th Street, Philadelphia, PA, 19122, USA, , United States

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 ?-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.

Cancers (Basel) 13 (21)