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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Structure-Guided Design of a Small-Molecule Activator of Sirtuin-3 that Modulates Autophagy in Triple Negative Breast

Jin Zhang1,2, Ling Zou1, Danfeng Shi1,3

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.

Journal of Medicinal Chemistry
|October 4, 2021
PubMed

Insights

Researchers discovered compound 33c, a specific activator of Sirtuin-3 (SIRT3), which inhibits triple-negative breast cancer (TNBC) growth by modulating autophagy. This finding offers a potential new therapeutic strategy for TNBC drug development.

Area of Science:

  • Mitochondrial biology
  • Cancer research
  • Drug discovery

Background:

  • Sirtuin-3 (SIRT3) is a mitochondrial protein deacetylase implicated in various human cancers.
  • SIRT3 positively regulates autophagy, a cellular degradation process, in cancer cells.
  • Activating SIRT3-modulated autophagy presents a potential therapeutic strategy for cancer drug development.

Purpose of the Study:

  • To discover a small-molecule activator of SIRT3.
  • To investigate the effect of SIRT3 activation on triple-negative breast cancer (TNBC) cells.
  • To explore the potential of pharmacological SIRT3 activation as a therapeutic approach for TNBC.

Main Methods:

  • Structure-guided design and high-throughput screening were employed to identify SIRT3 activators.
  • Compound 33c (ADTL-SA1215) was identified as a specific SIRT3 activator.
  • The effects of compound 33c on MDA-MB-231 breast cancer cells were evaluated both in vitro and in vivo, focusing on proliferation, migration, and autophagy/mitophagy pathways.

Main Results:

  • Compound 33c was identified as a specific small-molecule activator of SIRT3 with deacetylase activity.
  • Compound 33c inhibited the proliferation and migration of human breast carcinoma MDA-MB-231 cells.
  • These inhibitory effects were mediated through SIRT3-driven autophagy and mitophagy signaling pathways.

Conclusions:

  • Pharmacological activation of SIRT3 is a potential therapeutic strategy for triple-negative breast cancer (TNBC).
  • Compound 33c is a first-in-class specific small-molecule activator of SIRT3.
  • Compound 33c holds promise for future cancer drug development, particularly for TNBC.

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