Potent and Selective EphA4 Agonists for the Treatment of ALS. Issue 3 (16th March 2017)

• Record Type: Journal Article
• Authors: Wu, Bainan; De, Surya K.; Kulinich, Anna; Salem, Ahmed F.; Koeppen, Jordan; Wang, Rengang; Barile, Elisa; Wang, Si; Zhang, Dongxiang; Ethell, Iryna; Pellecchia, Maurizio
• Is Part Of: Cell chemical biology. Volume 24:Issue 3(2017)
• Page Start: 293
• Page End: 305
• Publication Date: 2017-03-16
• Subjects: EphA4 -- ALS -- HTS by NMR -- drug discovery -- ephrin; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.01.006
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: We report a novel, potent, and selective ligand targeting the EphA4 receptor Binding of the ligand is selective and enthalpy driven as verified by ITC The agent acts as an EphA4 agonist in primary neurons The agent is very efficacious in delaying the progression of ALS in a mouse model Abstract : Wu et al. report on the design and characterization of a novel, bona fide, potent, and selective ligand targeting the EphA4 receptor that is very efficacious in delaying the progression of ALS in mouse models.