Identification of a cytisine-based EED-EZH2 protein-protein interaction inhibitor preventing metastasis in triple-negative breast cancer cells

Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly triple-negative cancer (TNBC), and critical for cell invasion. It interacts with embryonic ectoderm development (EED) maintaining stem cells (CSC) epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association EZH2 EED promotes catalytic activity EZH2, inhibiting EED-EZH2 interaction a potential therapeutic strategy treating EZH2-dependent cancer. Although several protein-protein (PPI) inhibitors have been developed, few target EED. Here, we identified that cytisine derivative compound ( 1 ) potently binds EED, thus blocking PPI. Compound was found to inhibit proliferation suppress growth 3D tumor spheres TNBC cells. Moreover, by reversing EMT decreasing ratio CSCs, inhibited metastasis invasion ability. Therefore, targeting disrupt PPI may provide new approach To our knowledge, first cytisine-based inhibitor preventing This study avenue more efficacious treatment.