Structure-Based Discovery of the First Inhibitor Targeting the Talin2-β-integrin Interaction with Potent Antitumor Activity in Breast Cancer Models.

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 ( = 8.05 ± 0.17 nM) and favorable 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 antitumor activity without obvious toxicity. Peptide-2 exhibited favorable serum stability and pharmacokinetic characteristics. In conclusion, Peptide-2 is a novel inhibitor that offers a potential new strategy for breast cancer therapy.