Structure-Based Discovery of the First Inhibitor Targeting the Talin2-β-integrin Interaction with Potent In Vivo...

The talin2-β-integrin interaction modulates focal adhesion dynamics, promoting tumor cell migration and invasion, and thus represents an attractive anticancer target. Here, we identified the first talin2-β-integrin peptide inhibitor using structure-based virtual screening. Peptide-2 exhibited nanomolar binding affinity for talin2 (K_d = 8.05 ± 0.17 nM) and favorable in vitro selective inhibition. Molecular dynamics (MD) simulations indicated that Peptide-2 binds stably to talin2. Further studies showed that Peptide-2 significantly suppressed the proliferation, migration, and invasion of MDA-MB-231 cells as well as tube formation in HUVECs, with no significant toxicity toward normal cells. It inhibited FAK phosphorylation at Y397 and Y576, and displayed good cellular uptake and cytoplasmic localization. Moreover, Peptide-2 showed strong in vivo antitumor activity without obvious toxicity. Peptide-2 exhibited favorable in vitro serum stability and in vivo pharmacokinetic characteristics. In conclusion, Peptide-2 is a novel inhibitor that offers a potential new strategy for breast cancer therapy.