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

  • J Med Chem. 2021 Oct 14;64(19):14192-14216. doi: 10.1021/acs.jmedchem.0c02268.
Jin Zhang  1  2 ,  Ling Zou  1 ,  Danfeng Shi  1  3 ,  Jie Liu  1 ,  Jifa Zhang  1 ,  Rongyan Zhao  4 ,  Guan Wang  1 ,  Lan Zhang  4 ,  Liang Ouyang  1 ,  Bo Liu  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 2. School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
  • 3. Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China.
  • 4. School of Life Science and Engineering, Southwest Jiaotong University Chengdu, Chengdu 610031, China.
PMID: 34605238 DOI: 10.1021/acs.jmedchem.0c02268
Abstract

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.

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