Structure-Guided Design of a Small-Molecule Activator of Sirtuin‑3 that Modulates Autophagy in Triple Negative Breast Cancer

Sirtuin-3 (SIRT3) is an NAD⁺-dependent protein deacetylase localized primarily in the mitochondria with many links to different types of human cancers. Autophagy, which is a highly conserved lysosomal degradation process in eukaryotic cells, has been recently reported to be positively regulated by SIRT3 in cancer; therefore, activating SIRT3-modulated autophagy may be a promising strategy for drug discovery. In this study, we discovered a small-molecule activator of SIRT3 compound 33c (ADTL-SA1215) with specific SIRT3 deacetylase activity by structure-guided design and high-throughput screening. Subsequently, compound 33c inhibited the proliferation and migration of human breast carcinoma MDA-MB-231 cells by SIRT3-driven autophagy/mitophagy signaling pathways in vitro and in vivo. Collectively, these results demonstrate that pharmacological activation of SIRT3 is a potential therapeutic approach of triple negative breast cancer (TNBC). More importantly, compound 33c may be a first-in-class specific small-molecule activator of SIRT3 that would be utilized for future cancer drug development.