Targefrin: A Potent Agent Targeting the Ligand Binding Domain of EphA2

Overexpression of the receptor tyrosine kinase EphA2
is invariably
associated with poor prognosis and development of aggressive metastatic
cancers. Guided by our recently solved X-ray structure of the complex
between an agonistic peptide and EphA2-LBD, we report on a novel agent,
targefrin, that binds to EphA2-LBD with a 21 nM dissociation constant
by isothermal titration calorimetry and presents an IC50 value of 10.8 nM in a biochemical assay. In cell-based assays, a
dimeric version of the agent is as effective as the natural dimeric
ligands (ephrinA1-Fc) in inducing cellular receptor internalization
and degradation in several pancreatic cancer cell lines. When conjugated
with chemotherapy, the agents can effectively deliver paclitaxel to
pancreatic cancers in a mouse xenograft study. Given the pivotal role
of EphA2 in tumor progression, we are confident that the agents reported
could be further developed into innovative EphA2-targeting therapeutics.