Abstract
Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and cellular level. In particular, we propose a structural model for the mechanism of receptor activation by dimeric agents and characterize the effect of most potent compounds in inducing EphA2 activation and degradation in a pancreatic cancer cell line. These cellular studies indicate that the pro-migratory effects induced by the receptor can be reversed in EphA2 knockout cells, by treatment with either a dimeric natural ligand (ephrinA1-Fc), or by our synthetic agonistic dimers. Based on these data we conclude that the proposed agents hold great potential as possible therapeutics in combination with standard of care, where these could help suppressing a major driver for cell migration and tumor metastases. Finally, we also found that, similar to ephrinA1-Fc, dimeric agents cause a sustained internalization of the EphA2 receptor, hence, with proper derivatizations, these could also be used to deliver chemotherapy selectively to pancreatic tumors.
Highlights
Pancreatic cancer is an extremely aggressive and deadly disease, which accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths
Unlike general chemotherapy, targeted therapies focus on attacking cancer-specific pathways that contribute to cell proliferations, suppression of apoptosis, or cell migration, all contributing to the aggressiveness of pancreatic cancer
Therapeutic targeting of the EphA2-LBD has been pursued in recent years by a variety of approaches [27,32,37,38,39,40,41,42,43,44,45,46,47,48]
Summary
Pancreatic cancer is an extremely aggressive and deadly disease, which accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Current therapeutic strategies include treatment with 4-drugs: fluorouracil, leucovorin, irinotecan and oxaliplatin [1], gemcitabine or, more recently, gemcitabine plus abraxane (nanoparticle albumin-bound paclitaxel) [2]. While these treatments have significant effect on patients’ overall survival, their therapeutic impact remains modest [3,4]. Unlike general chemotherapy, targeted therapies focus on attacking cancer-specific pathways that contribute to cell proliferations, suppression of apoptosis, or cell migration, all contributing to the aggressiveness of pancreatic cancer. One such emerging family of targets are the Eph receptors. We focused on further investigating dimeric versions of these agonistic agents in pancreatic cancer cells, compared to a dimeric natural ligand (ephrinA1-Fc) and to EphA2 knockout cells
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