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

SIMPLE SUMMARY: In the last ten years, the human helicase protein DDX3X turned out to be an extremely interesting target for the development of potential anticancer drugs. Herein, we discovered BA103, a novel specific inhibitor of the helicase binding site of DDX3X, which is characterized by broad-spectrum anticancer activity. BA103 revealed promising tolerability in fibroblasts and good pharmacokinetic properties. Furthermore, BA103 was able to decrease the expression of β-catenin and to reduce tumor migration. Its capability to pass the blood–brain barrier led us to investigate its potential against glioblastoma, which is a high refractory disease with poor prognosis. High efficacy was proven in both xenograft and orthotopic animal models. ABSTRACT: 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.