A Small-Molecule SIRT2 Inhibitor That Promotes K-Ras4a Lysine Fatty-Acylation

Nicole A. Spiegelman, Jun Young Hong, Jing Hu, Hui Jing, Miao Wang, Ian R. Price, Ji Cao, Min Yang, Xiaoyu Zhang, Hening Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


SIRT2, a member of the sirtuin family of protein lysine deacylases, has been identified as a promising therapeutic target for treating cancer. In addition to catalyzing deacetylation, SIRT2 has recently been shown to remove fatty acyl groups from K-Ras4a and promote its transforming activity. Among the SIRT2-specific inhibitors, only the thiomyristoyl lysine compound TM can weakly inhibit the demyristoylation activity of SIRT2. Therefore, more potent small-molecule SIRT2 inhibitors are needed to further evaluate the therapeutic potential of SIRT2 inhibition, and to understand the function of protein lysine defatty-acylation. Herein we report a SIRT2 inhibitor, JH-T4, which can increase K-Ras4a lysine fatty acylation. This is the first small-molecule inhibitor that can modulate the lysine fatty acylation levels of K-Ras4a. JH-T4 also inhibits SIRT1 and SIRT3 in vitro. The increased potency of JH-T4 is likely due to the formation of hydrogen bonding between the hydroxy group and SIRT1, SIRT2, and SIRT3. This is further supported by in vitro studies with another small-molecule inhibitor, NH-TM. These studies provide useful insight for future SIRT2 inhibitor development.

Original languageEnglish (US)
Pages (from-to)744-748
Number of pages5
Issue number7
StatePublished - Apr 3 2019
Externally publishedYes


  • SIRT1
  • SIRT2
  • cancer
  • inhibitors
  • lysine fatty acylation
  • sirtuins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


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