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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity
Shenzhen Huang1, Chunli Song2, Xiang Wang3
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
Abstract:
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50 value of 1.3 μM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, SR86 showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of SR86, it could serve as a promising lead compound, hence deserving further studies.
Insights
Researchers discovered a novel SIRT2 inhibitor, SR86, with a unique structure. This compound shows high selectivity for SIRT2 and effectively inhibits breast cancer cell viability, making it a promising lead for further drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase implicated in diseases like cancer and neurodegeneration.
- Small molecule inhibitors targeting SIRT2 are of significant therapeutic interest.
- Developing selective SIRT2 inhibitors is a key research objective.
Purpose of the Study:
- To screen for and identify novel small molecule inhibitors of SIRT2.
- To characterize the activity, selectivity, and mechanism of action of newly discovered compounds.
- To evaluate the potential of novel SIRT2 inhibitors as therapeutic agents, particularly in cancer.
Main Methods:
- Utilized a consensus docking/scoring strategy for high-throughput screening.
- Performed structural optimization and structure-activity relationship (SAR) analysis.
- Conducted in vitro enzymatic assays, cellular assays (MCF-7 breast cancer cells), and Western blot analysis.
Main Results:
- Identified a novel SIRT2 inhibitor, SR86 (2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide), with an IC50 of 1.3 μM.
- SR86 demonstrated high selectivity for SIRT2 over SIRT1 and SIRT3.
- SR86 exhibited potent anti-viability activity against MCF-7 breast cancer cells and inhibited α-tubulin deacetylation.
Conclusions:
- SR86 represents a novel chemical scaffold with promising SIRT2 inhibitory activity and selectivity.
- The compound's efficacy in cellular assays suggests potential therapeutic applications, particularly in breast cancer.
- SR86 warrants further investigation as a lead compound for developing new treatments for SIRT2-related diseases.
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