Therapeutic potential of targeting the Eph/ephrin signaling complex

The Eph-ephrin signaling pathway mediates developmental processes and the proper functioning of the adult human body. This distinctive bidirectional signaling pathway includes a canonical downstream signal cascade inside the Eph-bearing cells, as well as a reverse signaling in the ephrin-bearing cells. The signaling is terminated by ADAM metalloproteinase cleavage, internalization, and degradation of the Eph/ephrin complexes. Consequently, the Eph-ephrin-ADAM signaling cascade has emerged as a key target with immense therapeutic potential particularly in the context of cancer. An interesting twist was brought forth by the emergence of ephrins as the entry receptors for the pathological Henipaviruses, which has spurred new studies to target the viral entry. The availability of high-resolution structures of the multi-modular Eph receptors in complexes with ephrins and other binding partners, such as peptides, small molecule inhibitors and antibodies, offers a wealth of information for the structure-guided development of therapeutic intervention. Furthermore, genomic data mining of Eph mutants involved in cancer provides information for targeted drug development. In this review we summarize the distinct avenues for targeting the Eph-ephrin signaling pathway, including its termination by ADAM proteinases. We highlight the latest developments in Eph-related pharmacology in the context of Eph-ephrin-ADAM-based antibodies and small molecules. Finally, the future prospects of genomics- and proteomics-based medicine are discussed.