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

• Published in: Journal of medicinal chemistry Vol. 65; no. 22; pp. 15443 - 15456
• Main Authors: Baggio, Carlo, Udompholkul, Parima, Gambini, Luca, Pellecchia, Maurizio
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-11-2022
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Humans; Ligands; Mice; Peptides - pharmacology; Receptor Protein-Tyrosine Kinases; Receptor, EphA2 - drug effects; Receptor, EphA2 - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01391

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.