GZD2202, a novel TrkB inhibitor, suppresses BDNF-mediated proliferation and metastasis in neuroblastoma models

J Drug Target. 2019 Apr;27(4):442-450. doi: 10.1080/1061186X.2018.1533964. Epub 2018 Oct 30.

Abstract

Collective data suggest tropomyosin-related kinase B (TrkB), which is correlated with the growth, migration and poor prognosis of neuroblastoma (NB), is a potential target for NB target therapy. Several Phase I/II pan-Trk inhibitors display impressive clinical outcomes but still no drug has been approved for general use. In this paper, we report a novel structural TrkB inhibitor GZD2202, a structural derivative of our previously identified DDR1 antagonists. GZD2202 demonstrates a moderate selectivity between Trk B/C and TrkA. GZD2202 suppresses the brain-derived neurotrophic factor (BDNF) -mediated TrkB signalling pathway, proliferation, migration and invasion in SH-SY5Y-TrkB neuroblastoma cells, and causes about 36.1% growth inhibition in a SH-SY5Y-TrkB neuroblastoma xenograft model.

Keywords: BDNF; GZD2202; Tropomyosin receptor kinase B; neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, trkB / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Brain-Derived Neurotrophic Factor
  • Protein Kinase Inhibitors
  • BDNF protein, human
  • Receptor, trkB