Targeting Eph receptors with chemical compounds and peptides

Abstract

The Eph receptors are a large family of tyrosine kinases involved in many biological processes and have recently emerged as promising drug target candidates. Indeed, they have been implicated in numerous pathological processes, including cancer progression and metastasis, pathological forms of angiogenesis and inhibition of spinal cord regeneration after injury. Therefore, inhibitors of Eph receptors function could be useful for diverse medical applications, in addition to helping elucidate the mechanism of receptor-ligand interaction. In this study we applied two different screening approaches, high throughput screening and combinatorial library screening, to the identification of chemical compounds that target EphA4 and EphA2. Two 2,5-dimethylpyrrolyl benzoic acid derivatives were identified in the high throughput screen for EphA4 antagonists. These compounds selectively inhibit ephrin binding to EphA4 and EphA2 and the characteristic biological activities of the two receptors, showing for the first time that the Eph receptors can be successfully targeted by small molecules. By combinatorial library screening, we also identified platinum(II) tetraamines as potential selective inhibitors of EphA2 activity. Finally, we modified TNYL-RAW, a potent peptide antagonist for EphB4, in order to improve its stability and delay its in vivo clearance from the blood circulation by coupling it with poly ethylene glycol (PEG) or the Fc portion of human IgG.