In absence of its ephrin ligands, the EphA2 receptor, overexpressed in most solid tumors, triggers cancer cell migration and invasion, leading to widespread metastases. These pro-oncogenic effects of the un-ligated EphA2 receptor can be reversed by ligand stimulation, that in turn triggers intrinsic tumor suppressive signaling pathways. Hence, the development of small molecule EphA2 agonistic agents, thus capable of mimicking the ephrin ligands, could be translated in potentially effective anti-metastatic agents. Moreover, given that receptor activation causes its internalization via a lysosomal mechanism, EphA2 agonistic agents could be used to deliver chemotherapy selectively to EphA2 expressing tumors. In recent years, we pursued the design, synthesis, and characterization of potent and effective EphA2 agonistic peptides, we termed targefrins. Aided by biophysical studies including NMR spectroscopy, X-ray crystallography, and isothermal titration calorimetry, we derived potent and effective EphA2 agonistic agents targeting its ligand binding domain with low nanomolar affinity. We observed that targefrins can deliver their cargo at tumor sites using in vivo imaging and efficacy studies in orthotopic models of breast, prostate, and pancreatic cancers. These studies strongly suggest that the approach could lead to effective and innovative anti-metastatic treatments for aggressive tumors.

Targeted delivery of chemotherapy via targefrins, EphA2 agonistic peptides

ACS Spring Meeting 2021

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