RRC ID 6812
著者 Oikawa T, Unno Y, Matsuno K, Sawada J, Ogo N, Tanaka K, Asai A.
タイトル Identification of a small-molecule inhibitor of the interaction between Survivin and Smac/DIABLO.
ジャーナル Biochem Biophys Res Commun
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.
巻・号 393(2)
ページ 253-8
公開日 2010-3-5
DOI 10.1016/j.bbrc.2010.01.113
PII S0006-291X(10)00176-2
PMID 20117083
MeSH Antibiotics, Antineoplastic / pharmacology Apoptosis Regulatory Proteins Cell Proliferation / drug effects Doxorubicin / pharmacology Drug Synergism Flavins / chemistry Flavins / isolation & purification Flavins / pharmacology* High-Throughput Screening Assays* Humans Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins / antagonists & inhibitors* Intracellular Signaling Peptides and Proteins / metabolism Microtubule-Associated Proteins / antagonists & inhibitors* Microtubule-Associated Proteins / metabolism Mitochondrial Proteins / antagonists & inhibitors* Mitochondrial Proteins / metabolism Survivin
IF 2.985
引用数 16
WOS 分野 BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 DU145(RCB2143)