Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors.
Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors.
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DOI：
10.1021/jm4018064
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发表时间：
2014-04-24
影响因子：
7.3
通讯作者：
Simon JA
中科院分区：
文献类型：
--
作者：
Mahajan SS;Scian M;Sripathy S;Posakony J;Lao U;Loe TK;Leko V;Thalhofer A;Schuler AD;Bedalov A;Simon JA
Sirtuins are a family of NAD+-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.
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影响因子：
7.3
作者：
Suzuki, Takayoshi;Khan, Mohammed Naseer Ahmed;Miyata, Naoki
通讯作者：
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影响因子：
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作者：
Burnett, Camilla;Valentini, Sara;Cabreiro, Filipe;Goss, Martin;Somogyvari, Milan;Piper, Matthew D.;Hoddinott, Matthew;Sutphin, George L.;Leko, Vid;McElwee, Joshua J.;Vazquez-Manrique, Rafael P.;Orfila, Anne-Marie;Ackerman, Daniel;Au, Catherine;Vinti, Giovanna;Riesen, Michele;Howard, Ken;Neri, Christian;Bedalov, Antonio;Kaeberlein, Matt;Soti, Csaba;Partridge, Linda;Gems, David
通讯作者：
Gems, David
影响因子：
7.3
作者：
Posakony, J;Hirao, M;Bedalov, A
通讯作者：
Bedalov, A
影响因子：
4.8
作者：
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通讯作者：
Ahn, Kay
影响因子：
7.3
作者：
Neugebauer, Robert C.;Uchiechowska, Urszula;Jung, Manfred
通讯作者：
Jung, Manfred