Structure-based discovery of a novel allosteric activator of ATG4B for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is highly malignant and lacks effective therapeutic drugs. ATG4B, a critical cysteine protease in autophagy, regulates LC3B processing and recycling to promote autophagosome formation, and its activation represents a promising therapeutic strategy for cancer. Based on structure-based drug design, this study conducted virtual screening of the SPECS compound library and optimized the structure through structure-activity relationship analysis, obtaining a novel ATG4B allosteric activator, 16a. This compound activates ATG4B and induces autophagy, significantly inhibiting the proliferation and migration of TNBC cells both in vitro and in vivo. In conclusion, this study has identified the first allosteric small-molecule activator targeting ATG4B, which not only provides a powerful tool molecule for in-depth exploration of autophagy regulation in TNBC treatment, but also lays an important foundation for the development of innovative drugs based on the autophagy activation mode.