Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation

Cell Chem Biol. 2018 Jun 21;25(6):775-786.e5. doi: 10.1016/j.chembiol.2018.03.012. Epub 2018 Apr 26.


Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients.

Keywords: G protein-coupled receptor; GPCR; GPR17; HAMI3379; demyelinating disease; drug repurposing; label-free dynamic mass redistribution; oligodendrocyte; orphan GPCR; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cyclohexanecarboxylic Acids / chemistry
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Repositioning*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Oligodendroglia / cytology*
  • Oligodendroglia / drug effects*
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology*
  • Propionates / chemistry
  • Propionates / pharmacology
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship


  • 2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid
  • 3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-(cyclohexyloxy)butoxy)phenyl)propoxy)benzoic acid
  • Cyclohexanecarboxylic Acids
  • GPR17 protein, human
  • Indoles
  • Phthalic Acids
  • Propionates
  • Receptors, G-Protein-Coupled