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.