Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University, 33720 Tampere, Finland.
BioMeditech and Tays Cancer Center, Tampere University, Hospital, P.O. Box 553, 33101 Tampere, Finland.
J Med Chem. 2021 Aug 12;64(15):10908-10918. doi: 10.1021/acs.jmedchem.1c00277. Epub 2021 Jul 25.
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, , with a glide score of -8.390 was synthesized through a multicomponent Petasis borono-Mannich reaction. The -GPR17 interaction leads to a rapid decrease of cAMP and Ca. exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC 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.
发现一种潜在的配体靶向 G 蛋白偶联受体 17（GPR17）对于开发针对多形性胶质母细胞瘤（GBM）的化学治疗剂非常重要。我们使用基于配体和结构的化学信息学与实验方法的整合，来鉴定用于 GBM 治疗的潜在 GPR17 配体。在这里，我们使用超过 6000 种吲哚啉衍生物的分子对接，鉴定出一种新型吲哚啉衍生的酚性曼尼希碱作为 GPR17 的激动剂。其中一个排名前十的命中分子 ，具有 -8.390 的 Glide 评分，通过多组分 Petasis 硼烷-Mannich 反应合成。 -GPR17 相互作用导致 cAMP 和 Ca 的快速减少。 以剂量依赖的方式对 GBM 细胞表现出细胞毒性作用，IC 为 85 μM，而已知的激动剂 MDL29,951 则几乎没有作用。我们的研究结果表明，酚性曼尼希碱可能是比 MDL29,951 更好的 GPR17 激动剂，进一步揭示它们的药理学特性可能会增强创新的 GBM 治疗效果。
