Computer-Aided Design of Novel Antagonists of the EphA2 Receptor

The Eph receptors are a large family of receptor tyrosine kinases, and their activity and downstream signaling ability are stimulated by the binding of cell membrane ligands known as ephrins [1]. A growing body of evidence suggests that the pharmacological modulation of the Eph-ephrin system may lead to innovative therapies for the treatment of solid tumors and neurodegenerative disorders [2]. However, the conclusive validation of Eph receptors as a drug targets is hampered by the lack of pharmacological tools featured by PD and PK profiles suitable for in vivo administration. The discovery of small molecules able to disrupt the Eph-ephrin interaction is a challenging task, due to the large size of the protein interacting surfaces and the lack of specialized chemical libraries to be used in HTS campaigns. Despite these shortcomings, we recently identified lithocholic acid (LCA) as a micromolar antagonist of the EphA2 receptor by means of an ELISA-based screening [2]. In the present talk, the results of our medicinal chemistry efforts devoted to the PD-optimization of LCA will be presented [3,4]. Details of the computational strategies applied to guide the synthesis of novel compounds will be discussed along with an analysis of the structure-activity relationships.