Eph receptors represent the largest subgroup of the receptor tyrosine kinase family and act in several physiological and pathological processes. Among them, EphA2 has received the greatest attention and its role in cancer has been extensively analyzed. Indeed, EphA2 is over-expressed in many cancer types and exhibits several pro-cancer activities thus, it represents a very challenging and attractive target for the development of novel therapeutic compounds.

The process of ligand-induced receptor endocytosis and the consequent degradation have been exploited as a route to reduce tumor malignancy. In malignant breast cancer cells, the lipid phosphatase Ship2 plays a crucial inhibitory role of EphA2 endocytosis. Ship2 is engaged at the receptor site through a heterotypic Sam-Sam association with the C-terminal Sam domain of EphA2 (EphA2-Sam). Structural and interaction studies indicated that Ship2-Sam binds EphA2-Sam by adopting a canonical “Mid-Loop/End-Helix” interaction model. Further in vitro cell-based assays showed that the EphA2-Sam/Ship2-Sam association produces mainly pro-oncogenic outcomes.

Nevertheless, the adaptor protein Odin, a member of the ANKS (Ankryn repeat and Sam domain containing) family, also plays an inhibitory role of EphA2-receptor degradation through its Sam domains. Odin possesses two tandem Sam domains (Sam1 and Sam2) and Odin-Sam1 is indeed able to bind EphA2-Sam adopting an interaction structure topology identical to that observed for the EphA2-Sam/Ship2-Sam complex.

Goal

Due to the possible correlation between enhanced EphA2 receptor endocytosis/degradation and reduced tumor malignancy, molecules capable of inhibiting its heterotypic Sam-Sam associations, could work as potential anti-cancer therapeutics.

The specific aims of this project are: 1) Structure-based design and evaluation of peptides and/or peptidomimetics able to avoid formation of the Ship2-Sam/EphA2-Sam and/or Odin-Sam1/EphA2-Sam complexes; 2) Analysis of the efficacy of the designed molecules in modulating EphA2 receptor endocytosis and subsequent degradation.

Figures:

Figure Caption. Peptides targeting Sam-Sam interactions involving EphA2 might work as anticancer agents. The 3D structures of different Sam domains are shown; the EphA2-Sam “End-Helix” interface is colored white and positively charged residues important for Sam-Sam associations are reported in blue; the “Mid-Loop” interfaces of Ship2-Sam and Odin-Sam1 are highlighted in blue with negatively charged residues, that are involved into intermolecular  contacts, shown in red.