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

[Image: see text] 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 Ca(2+). CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC(50) 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.