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Published on: April 9, 2021
A Small-Molecule SIRT2 Inhibitor That Promotes K-Ras4a Lysine Fatty-Acylation
Nicole A Spiegelman1, Jun Young Hong1, Jing Hu1
1Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
Abstract:
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.
Insights
Researchers developed JH-T4, a novel small-molecule inhibitor targeting SIRT2 (sirtuin 2), to address cancer therapy. This inhibitor modulates K-Ras4a lysine fatty acylation, offering new therapeutic avenues.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- SIRT2 (sirtuin 2) is a protein lysine deacylase and a potential cancer therapeutic target.
- SIRT2 removes fatty acyl groups from K-Ras4a, promoting cancer-driving activity.
- Existing SIRT2 inhibitors lack sufficient potency for therapeutic evaluation.
Purpose of the Study:
- To develop a potent small-molecule inhibitor of SIRT2.
- To investigate the role of SIRT2 in K-Ras4a lysine fatty acylation.
- To explore novel therapeutic strategies for cancer by targeting SIRT2.
Main Methods:
- Synthesis and characterization of the novel SIRT2 inhibitor JH-T4.
- In vitro assays to assess the inhibitory activity of JH-T4 against SIRT2, SIRT1, and SIRT3.
- Evaluation of JH-T4's effect on K-Ras4a lysine fatty acylation levels.
Main Results:
- JH-T4 effectively inhibits SIRT2 and increases K-Ras4a lysine fatty acylation.
- This study reports the first small-molecule inhibitor capable of modulating K-Ras4a lysine fatty acylation.
- JH-T4 also demonstrates inhibitory activity against SIRT1 and SIRT3 in vitro, potentially via hydrogen bonding.
Conclusions:
- JH-T4 represents a significant advancement in the development of SIRT2 inhibitors.
- Modulating K-Ras4a lysine fatty acylation is a viable strategy for cancer therapy.
- Further research into JH-T4 and similar compounds can guide future SIRT2 inhibitor design.
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