ArticleThe Journal of biological chemistry2008
Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 133 citations in OpenAlex.
- Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer.ChemMedChem · 2023Article
- Eph Receptors in Cancer.Biomedicines · 2023Review
- Ribonuclease 1 Enhances Antitumor Immunity against Breast Cancer by Boosting T cell Activation.International journal of biological sciences · 2023Article
- Development of an In-House EphA2 ELISA for Human Serum and Measurement of Circulating Levels of EphA2 in Hypertensive Patients with Renal Dysfunction.Diagnostics (Basel, Switzerland) · 2022Article
- EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.iScience · 2022Article
- The role of EphA7 in different tumors.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2022Review
- Review
- The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.Cellular & molecular biology letters · 2022Review
- A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis.Clinical and translational medicine · 2022Review
- NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.Journal of medicinal chemistry · 2021Article
- A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain.The Journal of biological chemistry · 2021Article
- Nogo-A-Δ20/EphA4 interaction antagonizes apoptosis of neural stem cells by integrating p38 and JNK MAPK signaling.Journal of molecular histology · 2021Article
- Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation.Nature communications · 2021Article
- Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation.International journal of molecular sciences · 2021Article
- EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke.The Journal of clinical investigation · 2020Article
- EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria.PLoS pathogens · 2020Article
- EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions.iScience · 2019Article
- Therapeutic potential of targeting the Eph/ephrin signaling complex.The international journal of biochemistry & cell biology · 2018Review
- Theoretical Model of EphA2-Ephrin A1 Inhibition.Molecules (Basel, Switzerland) · 2018Article
- Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs.Scientific reports · 2018Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases regulates a multitude of physiological and pathological processes. Despite the numerous possible research and therapeutic applications of agents capable of modulating Eph receptor function, no small molecule inhibitors targeting the extracellular domain of these receptors have been identified. We have performed a high throughput screen to search for small molecules that inhibit ligand binding to the extracellular domain of the EphA4 receptor. This yielded a 2,5-dimethylpyrrolyl benzoic acid derivative able to inhibit the interaction of EphA4 with a peptide ligand as well as the natural ephrin ligands. Evaluation of a series of analogs identified an isomer with similar inhibitory properties and other less potent compounds. The two isomeric compounds act as competitive inhibitors, suggesting that they target the high affinity ligand-binding pocket of EphA4 and inhibit ephrin-A5 binding to EphA4 with K(i) values of 7 and 9 mum in enzyme-linked immunosorbent assays. Interestingly, despite the ability of each ephrin ligand to promiscuously bind many Eph receptors, the two compounds selectively target EphA4 and the closely related EphA2 receptor. The compounds also inhibit ephrin-induced phosphorylation of EphA4 and EphA2 in cells, without affecting cell viability or the phosphorylation of other receptor tyrosine kinases. Furthermore, the compounds inhibit EphA4-mediated growth cone collapse in retinal explants and EphA2-dependent retraction of the cell periphery in prostate cancer cells. These data demonstrate that the Eph receptor-ephrin interface can be targeted by inhibitory small molecules and suggest that the two compounds identified will be useful to discriminate the activities of EphA4 and EphA2 from those of other co-expressed Eph receptors that are activated by the same ephrin ligands. Furthermore, the newly identified inhibitors represent possible leads for the development of therapies to treat pathologies in which EphA4 and EphA2 are involved, including nerve injuries and cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.