Targeting Eph receptors with peptides and small molecules: progress and challenges

Abstract

The Eph receptors are a large family of receptor tyrosine kinases. Their kinase activity and downstream signaling ability are stimulated by the binding of cell surface-associated ligands, the ephrins. The ensuing signals are bidirectional because the ephrins can also transduce signals (known as reverse signals) following their interaction with Eph receptors. The ephrin-binding pocket in the extracellular N-terminal domain of the Eph receptors and the ATP-binding pocket in the intracellular kinase domain represent potential binding sites for peptides and small molecules. Indeed, a number of peptides and chemical compounds that target Eph receptors and inhibit ephrin binding or kinase activity have been identified. These molecules show promise as probes to study Eph receptor/ephrin biology, as lead compounds for drug development, and as targeting agents to deliver drugs or imaging agents to tumors. Current challenges are to find (1) small molecules that inhibit Eph receptor-ephrin interactions with high binding affinity and good lead-like properties and (2) selective kinase inhibitors that preferentially target the Eph receptor family or subsets of Eph receptors. Strategies that could also be explored include targeting additional Eph receptor interfaces and the ephrin ligands.

Fig. 1

Current and potential strategies to target Eph receptors with peptides and small molecules. Molecules that target the ephrin-binding pocket inhibit ephrin binding, while molecules that target the ATP-binding site inhibit kinase activity. Other interfaces that could be targeted are those between the ephrin-binding domains, sushi domains, transmembrane segments and sterile alpha motifs (SAM) of two neighboring Eph receptor molecules (asterisks). Furthermore, inhibiting the binding of amyloid-β (A-β) or cytoplasmic signaling proteins, such as those containing SH2 domains, could more selectively affect only some Eph receptor activities.