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Published on: September 3, 2013
Design, synthesis and biological evaluation of prostate-specific membrane antigen (PSMA)-targeted SIRT2 inhibitors
Junhui Yu1, Zhicheng Gu1, Chuang Zhang1
1State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China.
Abstract:
Sirtuins belong to a specific class of enzymes called NAD+-dependent protein deacetylases. Among them, SIRT2 is predominantly localized in the cytoplasm and plays a vital role in tumor development and progression. As a result, it becomes an important target for the development of anticancer drugs. While SIRT2 inhibitors have shown broad-spectrum cytotoxicity against various cancer cells, their ability to inhibit the growth of certain cancers like prostate cancer has been limited, possibly due to insufficient targeting properties. To overcome this limitation, our goal was to target prostate-specific membrane antigen (PSMA), a valuable biomarker for prostate cancer, using lysine-urea-glutamic acid (KUE) as a PSMA ligand. This approach allowed us to systematically design new SIRT2 inhibitors. Evaluation showed that compound 17 exhibited superior inhibitory activity, improved targeting properties, and enhanced antiproliferative efficacy specifically in prostate cancer cells. These findings suggest a promising strategy for utilizing SIRT2 inhibitors in prostate cancer therapy.
Insights
New SIRT2 inhibitors targeting prostate-specific membrane antigen (PSMA) show promise for prostate cancer therapy. Compound 17 demonstrated enhanced efficacy and targeting in prostate cancer cells, overcoming limitations of previous inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sirtuins are NAD+-dependent deacetylases; SIRT2 is crucial in tumor progression.
- SIRT2 inhibitors show broad anticancer activity but limited efficacy in prostate cancer due to targeting issues.
Purpose of the Study:
- To develop novel SIRT2 inhibitors with improved targeting for prostate cancer.
- To leverage prostate-specific membrane antigen (PSMA) as a targeting biomarker.
Main Methods:
- Designed new SIRT2 inhibitors using a PSMA-targeting ligand (lysine-urea-glutamic acid).
- Evaluated compound efficacy, targeting, and antiproliferative effects in prostate cancer cells.
Main Results:
- Compound 17 displayed superior SIRT2 inhibitory activity.
- Compound 17 showed enhanced targeting and antiproliferative efficacy in prostate cancer cells.
- The PSMA-targeting strategy improved inhibitor performance.
Conclusions:
- Targeting PSMA with novel SIRT2 inhibitors offers a promising therapeutic strategy for prostate cancer.
- Compound 17 represents a potential lead for prostate cancer treatment development.
