Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.
Annalaura BraiValentina RivaLetizia ClementiLucia FalsittaClaudio ZamperiniVirginia SinigianiClaudio FestucciaSamantha SabettaDavide AielloCamilla RoselliAnna GarbelliClaudia Immacolata TrivisaniLaura MaccariFrancesca BugliSanguinetti MaurizioPierpaolo CalandroMario ChiarielloPaola QuarantaLorenzo BottaAdriano AngelucciGiovanni MagaMaurizio BottaPublished in: Cancers (2021)
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.
Keyphrases
- papillary thyroid
- transcription factor
- induced apoptosis
- cancer therapy
- epithelial mesenchymal transition
- stem cells
- signaling pathway
- cell proliferation
- white matter
- mesenchymal stem cells
- squamous cell carcinoma
- functional connectivity
- drug delivery
- atomic force microscopy
- cell cycle arrest
- brain injury
- resting state
- small molecule
- binding protein
- cell death
- mass spectrometry
- subarachnoid hemorrhage
- amino acid
- drug induced