Identification of a small-molecule inhibitor of the interaction between Survivin and Smac/DIABLO

Biochemical and Biophysical Research Communications
Tsuyoshi OikawaAkira Asai

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-molecu...Continue Reading

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Citations

Aug 21, 2013·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Bernd Groner, Astrid Weiss
Mar 20, 2012·Journal of Cancer Research and Clinical Oncology·Astrid WeissBernd Groner
Mar 5, 2013·Cancer Treatment Reviews·Mohane Selvaraj CoumarChun Hei Antonio Cheung
Nov 2, 2011·The International Journal of Biochemistry & Cell Biology·Jeffrey C HorowitzThomas H Sisson
Jan 29, 2013·Advances in Bioscience and Biotechnology·Thomas H SissonJeffrey C Horowitz
Feb 18, 2018·The Journal of Biological Chemistry·Timothy J BergmannMaurizio Molinari
May 8, 2019·Journal of Cellular Physiology·Parisa ZafariMahdi Taghadosi
Jun 30, 2019·Chemistry, an Asian Journal·Seong-Hyun ParkInjae Shin
Aug 24, 2019·Journal of Experimental & Clinical Cancer Research : CR·Fengzhi LiXiang Ling
May 26, 2017·Cellular & Molecular Biology Letters·Zakir KhanPrakash Singh Bisen
Feb 6, 2017·Biochemical and Biophysical Research Communications·Liyun YueLijian Hui

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