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

Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy

“…To achieve the hallmark of excessive cell proliferation, DEAD/H-box helicases are often overexpressed in cancer cells ( Table 1 ). For example, DDX3 is highly expressed in breast cancer ( 124 ), Ewing sarcoma ( 68 ), glioblastoma ( 125 ) and gallbladder carcinoma ( 126 ). DDX27 is upregulated in gastric tumors ( 94 ), colorectal cancer ( 127 ), and breast cancer ( 128 ).…”

DEAD-Box Helicase DDX3X as a Host Target against Emerging Viruses: New Insights for Medicinal Chemical Approaches

“…The replacement of tolyl terminus with polar substituents such as sulfonamides in compound 63 increases the inhibitory capability to 0.06 μM, as well as the replacement with isoquinoline (0.15 μM). Substitution of the atoms in the central ring led to compounds with similar activities . Additional modifications included replacement of the triazole ring with other pentatomic heterocycles (compounds 73 – 75 ), the most active compound was 74 , with an IC 50 of 0.07 μM …”

“…Substitution of the atoms in the central ring led to compounds with similar activities . Additional modifications included replacement of the triazole ring with other pentatomic heterocycles (compounds 73 – 75 ), the most active compound was 74 , with an IC 50 of 0.07 μM …”

“…Substitution of the atoms in the central ring led to compounds with similar activities. 55 Additional modifications included replacement of the triazole ring with other pentatomic heterocycles (compounds 73−75), the most active compound was 74, with an IC 50 of 0.07 μM. 55 The homology model generated was then used to screen several commercial databases, 56 including Asinex, Chembridge, InterbioScreen, and SPECS.…”

“…55 Additional modifications included replacement of the triazole ring with other pentatomic heterocycles (compounds 73−75), the most active compound was 74, with an IC 50 of 0.07 μM. 55 The homology model generated was then used to screen several commercial databases, 56 including Asinex, Chembridge, InterbioScreen, and SPECS. As a result, 10 compounds with helicase inhibitory values from 0.2 to 19.5 μM were discovered; 56 the most promising were 76 and 77.…”