Synthesis and Preclinical Validation of Novel Indole Derivatives as a GPR17 Agonist for Glioblastoma Treatment

The discovery of
a potential ligand-targeting G protein-coupled
receptor 17 (GPR17) is important for developing chemotherapeutic agents
against glioblastoma multiforme (GBM). We used the integration of
ligand- and structure-based cheminformatics and experimental approaches
for identifying the potential GPR17 ligand for GBM treatment. Here,
we identified a novel indoline-derived phenolic Mannich base as an
activator of GPR17 using molecular docking of over 6000 indoline derivatives.
One of the top 10 hit molecules, CHBC, with a glide score
of −8.390 was synthesized through a multicomponent Petasis
borono–Mannich reaction. The CHBC–GPR17
interaction leads to a rapid decrease of cAMP and Ca2+. CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent
manner with an IC50 of 85 μM, whereas the known agonist
MDL29,951 showed a negligible effect. Our findings suggest that the
phenolic Mannich base could be a better GPR17 agonist than MDL29,951,
and further uncovering their pharmacological properties could potentiate
an inventive GBM treatment.