A Caged Ret Kinase Inhibitor and its Effect on Motoneuron Development in Zebrafish Embryos

Sci Rep. 2015 Aug 24:5:13109. doi: 10.1038/srep13109.

Abstract

Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compounds by attaching photolabile groups to the exocyclic amino function. The most promising compound displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding Sites
  • Drug Design
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / embryology*
  • Humans
  • Light
  • Motor Neurons / drug effects*
  • Photolysis
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Zebrafish / embryology*

Substances

  • MAS1 protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Mas
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-ret
  • RET protein, human