Potent and Selective EphA4 Agonists for the Treatment of ALS

Cell Chem Biol. 2017 Mar 16;24(3):293-305. doi: 10.1016/j.chembiol.2017.01.006. Epub 2017 Feb 9.


Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacological tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments.

Keywords: ALS; EphA4; HTS by NMR; drug discovery; ephrin.

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Design
  • Half-Life
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Receptor, EphA4 / agonists*
  • Receptor, EphA4 / chemistry
  • Receptor, EphA4 / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism


  • Ligands
  • Protein Isoforms
  • Small Molecule Libraries
  • Superoxide Dismutase
  • Receptor, EphA4