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.
Bainan Wu  1 ,  Surya K De  2 ,  Anna Kulinich  2 ,  Ahmed F Salem  2 ,  Jordan Koeppen  2 ,  Rengang Wang  3 ,  Elisa Barile  2 ,  Si Wang  1 ,  Dongxiang Zhang  1 ,  Iryna Ethell  2 ,  Maurizio Pellecchia  4
Affiliations
  • 1. Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2. Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
  • 3. Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Brain Development, University of California San Diego, San Diego, CA 92090, USA.
  • 4. Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA. Electronic address: [email protected].
PMID: 28196613 DOI: 10.1016/j.chembiol.2017.01.006
Abstract

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.
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