Scientists Select Potent Agonists to Target EphA4 in ALS

EphA4 is emerging as a key obstacle in the repair and regeneration of motor neuronal axons. Blocking the activation of this receptor tyrosine kinase is showing promise as a potential treatment for spinal cord injury (Fabes et al., 2007; Goldshmit et al, 2011). And, more recently, this strategy has been shown to protect motor neurons in ALS at the preclinical stage (van Hoecke et al., 2012). But there are 9 EphA receptors. Many of them are produced in motor neurons. Researchers have simply been unable to identify potent small molecule EphA4 blockers of sufficient selectivity to evaluate as a treatment for the disease. And, peptide antagonists are difficult to develop due to their inherent instability in circulation.

Targeting EphA4, never follow. Researchers developed an EphA4 agonist that significantly extends survival of a SOD1 mouse model of the disease  (p < 0.01). The approach is distinct from existing approaches being developed that act as antagonists. These include EphA4-Fc and cyclic peptides. [Courtesy of Cell Chemical Biology, Wu et al., 2017.]

Now, a research team led by University of California’s Maurizio Pellecchia in Riverside, introduce a compound that binds EphA4 at nanomolar affinity with >10-fold selectivity over EphA3, the most highly-related receptor tyrosine kinase. The small molecule, known as 123C4, can penetrate the brain and upon intraperitoneal injection, can moderately extend the survival of a SOD1 G93A mouse model of the disease. The compound, which acts as an EphA4 agonist, appears to remove EphA4 from the surface of neurons by receptor-mediated endocytosis.

The strategy is speculated to help protect motor neurons in ALS by preventing ephrin B2 from activating EphA4 on its surfaces, enabling the repair of motor neurons damaged by the disease (Ren et al, 2013).

The study is published on February 8 in Cell Chemical Biology.

Researchers first identified EphA4 as a potential target of ALS by screening for protective genetic modifiers of the disease. The study, led by University of Leuven’s Wim Robberecht in Belgium, found that the levels of EphA4 inversely correlated with the survival time of people with the disease. The team first identified the receptor tyrosine kinase as a potential target of ALS because of its ability to extend the survival of a zebrafish model of SOD1 disease.

The strategy is now being optimized and is in the preclinical stage. The project is in collaboration with Iron Horse Therapeutics, a San Diego, California startup founded by GlaxoSmithKline in partnership with Avalon Ventures.


Wu B, De SK, Kulinich A, Salem AF, Koeppen J, Wang R, Barile E, Wang S, Zhang D, Ethell I, Pellecchia M. Potent and Selective EphA4 Agonists for the Treatment of ALS. Cell Chemical Biology. Published online February 9, 2017.

Fabes J, Anderson P, Brennan C, Bolsover S. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur J Neurosci. 2007 Nov;26(9):2496-505. [PubMed].

Goldshmit Y, Spanevello MD, Tajouri S, Li L, Rogers F, Pearse M, Galea M, Bartlett PF, Boyd AW, Turnley AM. EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS One. 2011;6(9):e24636. [PubMed].

Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B, Andersen PM, Al-Chalabi A, Thijs V, Turnley AM, van Vught PW, Veldink JH, Hardiman O, Van Den Bosch L, Gonzalez-Perez P, Van Damme P, Brown RH Jr, van den Berg LH, Robberecht W. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. 2012 Sep;18(9):1418-22. [PubMed].

Ren Z, Chen X, Yang J, Kress BT, Tong J, Liu H, Takano T, Zhao Y, Nedergaard M.Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter. Neuroscience. 2013 Jun 25;241:89-99. [PubMed].

Further Reading

Tognolini M, Incerti M, Lodola A. Are we using the right pharmacological tools to target EphA4?  ACS Chem Neurosci. 2014 Dec 17;5(12):1146-7. doi: 10.1021/cn500285h. [PubMed].


Image on the home page: EphA4-ephrin B complex. Bowden et al., 2009. Courtesy of Structure under CC-BY license.

disease-als EphA4 ephrinB2 geneticmodifier topic-preclinical topic-randd topic-researchmodels
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