title: Potent and Selective EphA4 Agonists for the Treatment of ALS.
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.
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kulinich
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Salem
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Koeppen
authors.affiliation: 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.
authors.forename: Rengang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Ethell
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA 92521, USA. Electronic address: maurizio.pellecchia@ucr.edu.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D036122:Receptor, EphA4 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase; D036122:Receptor, EphA4
keywords: ALS; EphA4; HTS by NMR; drug discovery; ephrin