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
References
Aug 1, 1997·Nature Medicine·G AmbrosiniD C Altieri
Dec 22, 1998·Nature·F LiD C Altieri
Nov 24, 1999·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M MonzóA Abad
Dec 10, 1999·Nature Cell Biology·F LiD C Altieri
Aug 10, 2000·Cell·C DuX Wang
Aug 10, 2000·Cell·A M VerhagenD L Vaux
Feb 15, 2001·Biochemistry·S ShinB H Oh
Oct 3, 2001·The Journal of Clinical Investigation·D GrossmanD C Altieri
Sep 10, 2002·The Journal of Biological Chemistry·Christina R ArntScott H Kaufmann
Sep 11, 2002·Molecular Biology of the Cell·Margaret A BoltonP Todd Stukenberg
Mar 28, 2003·The Journal of Biological Chemistry·Zhiyin SongMian Wu
Dec 31, 2003·Molecular Biology of the Cell·Zhiyin SongMian Wu
Oct 22, 2005·EMBO Reports·Gerben VaderSusanne M A Lens
Jan 11, 2007·Cancer Treatment Reviews·Emma J DeanCaroline Dive
Oct 25, 2007·Cell·A Arockia JeyaprakashElena Conti
Oct 31, 2007·Cancer Letters·Aki OguraOsamu Inanami
Dec 14, 2007·Nature Reviews. Cancer·Dario C Altieri
Jun 10, 2008·Protein Science : a Publication of the Protein Society·Changqing LiWuyuan Lu
Jun 30, 2009·Cancer Treatment Reviews·Bríd M RyanMichael J Duffy
Citations
Aug 27, 2013·PloS One·Kazuyuki TakakumaAkira Asai
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
Oct 5, 2015·European Journal of Medicinal Chemistry·Si-Han Sherman HoMei-Lin Go
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
Jul 25, 2012·Bioengineered·Bernd GronerLaura Mack
Jan 1, 2012·JAK-STAT·Corina BorghoutsBernd Groner
Feb 5, 2016·Biomaterials Science·Ragini JenkinsStephen H Foulger
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
May 1, 2021·Cancers·Thomas MohrAlexander Tolios