Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age
of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor
prognosis, and the median survival is generally less than 16-24 months independently from
the treatment received. Up to now, children with DIPG are treated with focal radiotherapy
alone or in combination with antitumor agents.
In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high
throughput screening of public libraries of compounds, to be endowed with cytotoxic activity
against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible
for its antiproliferative effect. The hypothesized targets were the Tumor necrosis
factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases
(ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors
(DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P
(ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together
with other two classes of compounds, namely ADEPs and D9, already known for their
antibiotic activity but noteworthy to be discussed and studied as potential “leads” for the development
of new drugs to be used in the treatment of DIPG.
In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic
activity is made, with particular attention to the specific interactions established with its targets
that also are intimately described. Pubmed published patents and clinical trial reports of
the last ten years were used as the bibliographic source.