4‐2 VHL‐Recruiting PROTAC Inhibits the Growth and Migration of Triple Negative Breast Cancer Cells by Triggering Pyroptosis Through Fas‐Mediated IL‐17 Signaling

Abstract

SND1 is an oncoprotein found to be overexpressed in breast cancer, especially in triple‐negative breast cancer(TNBC). In our previous study, a novel SND1‐interacting peptide 4‐2 was identified, exhibiting cytotoxicity to TNBC cells by inducing SND1 degradation. This study for the first time demonstrated the degradation of SND1 was proteasome‐dependent. A series of peptide 4‐2 derivatives were constructed using PROTAC technology. Among these, 4‐2 VHL‐recruiting PROTAC showed significantly increased SND1 degradation efficiency and higher anticancer activity to TNBC cells. The in vivo efficacy study suggested the D‐isoform of 4‐2VHL PROTAC suppressed the growth of TNBC cells in xenograft mouse model more effectively than peptide 4‐2. Mechanistically, 4‐2 VHL‐recruiting PROTAC was demonstrated to induce pyroptosis of TNBC cells through Fas‐mediated IL‐17signaling. This study provides a new lead compound for the development of theSND1‐targeted therapy via the proteolysis‐targeting system.