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Identification of a small-molecule inhibitor of the interaction between Survivin and Smac/DIABLO
Tsuyoshi Oikawa1, Yuka Unno, Kenji Matsuno
1University of Shizuoka, Yada, Suruga-ku, Japan.
Abstract:
The protein Survivin is selectively overexpressed in a variety of cancers, but not in normal tissues. It has been reported to be involved in cell survival and cell division. However, the molecular mechanisms involved in its function are not clear, although several binding partner proteins have been proposed to date. Here, we report the identification of a novel small molecule Survivin antagonist, which disrupts the Survivin-Smac/DIABLO interaction in cells. In order to identify Survivin-directed antagonists, we developed a high-throughput screening system based on AlphaScreen technology, which allows the identification of small molecules with the ability to inhibit the interaction of Survivin with Smac/DIABLO or INCENP in vitro. We screened chemical libraries, generated in-house, using this system and identified a 5-deazaflavin analog (compound 1) as a hit compound that selectively inhibited the interaction of Survivin with Smac/DIABLO but not INCENP. In cultured cells, compound 1 abrogated the formation of the complex between Survivin and Smac/DIABLO. In addition, this compound was able to sensitize cultured cells to doxorubicin-mediated DNA damage stress and synergistically enhance apoptotic cell death. Thus, the small-molecule inhibitor described here may serve as a proof-of-principle agent for discriminating between the multiple functions of Survivin.
Insights
Researchers identified a novel small molecule inhibitor that disrupts the Survivin-Smac/DIABLO interaction. This compound sensitizes cancer cells to chemotherapy, offering a potential strategy for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Survivin is overexpressed in many cancers, promoting cell survival and division.
- The precise molecular functions of Survivin are not fully understood.
- Identifying specific inhibitors is crucial for targeting cancer cells.
Purpose of the Study:
- To identify novel small molecule antagonists of Survivin.
- To investigate the disruption of Survivin interactions with binding partners.
- To evaluate the therapeutic potential of identified compounds in cancer cells.
Main Methods:
- Development of a high-throughput AlphaScreen assay to screen for inhibitors of Survivin-Smac/DIABLO or Survivin-INCENP interactions.
- Screening of in-house chemical libraries.
- Cell-based assays to confirm compound efficacy and mechanism of action.
Main Results:
- A 5-deazaflavin analog (compound 1) was identified as a selective inhibitor of the Survivin-Smac/DIABLO interaction.
- Compound 1 disrupted the Survivin-Smac/DIABLO complex in cultured cells.
- Compound 1 sensitized cells to doxorubicin-induced DNA damage and enhanced apoptosis.
Conclusions:
- A novel small molecule inhibitor targeting the Survivin-Smac/DIABLO interaction was discovered.
- This inhibitor demonstrates potential for sensitizing cancer cells to chemotherapy.
- The findings provide a proof-of-concept for targeting specific Survivin functions.
