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Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

Asad Ali Shah1, Akihiro Ito, Akiko Nakata

  • 1Chemical Genetics Laboratory, RIKEN.

Biological & Pharmaceutical Bulletin
|October 12, 2016
PubMed

Insights

Researchers discovered a novel small molecule that selectively inhibits SIRT2, a protein implicated in cancer. This compound reduced breast cancer cell viability and shows potential as a targeted therapeutic agent.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase involved in critical cellular processes.
  • SIRT2 dysregulation is linked to various diseases, notably cancer.
  • Existing SIRT2 inhibitors lack structural novelty or exhibit off-target effects.

Purpose of the Study:

  • To identify and characterize a novel small molecule inhibitor of SIRT2.
  • To evaluate the compound's selectivity and cellular efficacy.
  • To assess its therapeutic potential in breast cancer treatment.

Main Methods:

  • Screening of a chemical library to identify SIRT2 inhibitors.
  • In vitro selectivity assays against other sirtuins (SIRT1, SIRT3) and histone deacetylases (HDAC1, HDAC6).
  • Assessment of compound effects on acetylation of eukaryotic translation initiation factor 5A (eIF5A), cell viability, and c-Myc expression in human breast cancer cells.

Main Results:

  • A novel small molecule inhibitor of SIRT2 was identified with a unique chemical structure.
  • The compound demonstrated high selectivity for SIRT2, inhibiting neither other sirtuins nor HDACs in vitro.
  • In cellular assays, the inhibitor increased eIF5A acetylation, reduced breast cancer cell viability, and decreased c-Myc expression.

Conclusions:

  • The novel small molecule is a potent and selective SIRT2 inhibitor.
  • The compound exhibits cellular effectiveness by modulating SIRT2 substrates and impacting cancer cell phenotypes.
  • This SIRT2 inhibitor holds promise for developing targeted therapies against breast cancers.

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