2. Academic Validation
  3. Synthesis and Preclinical Validation of Novel Indole Derivatives as a GPR17 Agonist for Glioblastoma Treatment

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

  • J Med Chem. 2021 Aug 12;64(15):10908-10918. doi: 10.1021/acs.jmedchem.1c00277.
Phung Nguyen 1 2,  Phuong Doan 1 2,  Tatu Rimpilainen 3,  Saravanan Konda Mani 4,  Akshaya Murugesan 1 5,  Olli Yli-Harja 6 7,  Nuno R Candeias 3 8,  Meenakshisundaram Kandhavelu 1 2
Affiliations

Affiliations

  • 1 Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University, 33720 Tampere, Finland.
  • 2 BioMeditech and Tays Cancer Center, Tampere University, Hospital, P.O. Box 553, 33101 Tampere, Finland.
  • 3 Faculty of Engineering and Natural Sciences, Tampere University, 33101 Tampere, Finland.
  • 4 Scigen Research and Innovation Pvt Ltd, Periyar Technology Business Incubator, Thanjavur, Tamil Nadu 613403, India.
  • 5 Department of Biotechnology, Lady Doak College, Thallakulam, 625002 Madurai, India.
  • 6 Computational Systems Biology Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, Finland.
  • 7 Institute for Systems Biology, 1441N 34th Street, Seattle, Washington 98103-8904, United States.
  • 8 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
PMID: 34304559 DOI: 10.1021/acs.jmedchem.1c00277
Abstract

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.

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