Structural basis for the activity of the RSK-specific inhibitor, SL0101
Structural basis for the activity of the RSK-specific inhibitor, SL0101
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DOI：
10.1016/j.bmc.2007.03.087
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发表时间：
2007-07-15
影响因子：
3.5
通讯作者：
Lannigan, Deborah A.
中科院分区：
文献类型：
--
作者：
Smith, Jeffrey A.;Maloney, David J.;Lannigan, Deborah A.
p90核糖体S6激酶（RSK）的不适当活性与各种人类癌症以及其他病理学有关。我们先前报道了天然产物山萘酚3-O-（3“，4”-二-O-乙酰基-α-L-吡喃鼠李糖苷）的分离、表征和合成，称为SL 0101 [Smith，J.A.; Poteet-Smith，C. E.的;徐，Y.; Errington，T. M.; Hecht，S. M.; Lannigan，D. A.癌症研究所，2005，65，1027-1034：Xu，Y.- M; Smith，J. A.; Lannigan，D.一、Hecht，S. M. Bioorg.医药化学，2006，14，3974-3977：Maloney，D. J.道：Hecht，S. M.组织通讯，2005，7，1097-1099]。SL 0101是RSK的有效和特异性抑制剂;因此，我们对该先导化合物的抑制活性的结构基础进行了分析。在体外激酶测定中，我们发现鼠李糖部分和4 '、5和7-羟基的酰化负责维持RSK与SL 0101的高亲和力相互作用。羟基可能通过其形成氢键的能力促进RSK结合。为了确定SL 0101衍生物是否对RSK的抑制具有特异性，我们分析了它们与正常人乳腺细胞系MCF-10A相比优先抑制人乳腺癌细胞系MCF-7生长的能力。我们先前已经验证了这种差异生长测定法作为分析RSK抑制剂特异性的方便读数[Smith，J.A.; Maloney，D. J.道：Clark，D. E.的;徐玉- M.; Hecht，S. M.; Lannigan，D. A. Bioorg.医学化学，2006，14，6034 -6042]。我们发现，酰化的鼠李糖部分是必不可少的保持选择性RSK抑制在完整的细胞。此外，SL 0101在完整细胞中的功效受到细胞摄取以及普遍存在的细胞内酯酶对鼠李糖部分上的乙酰基可能水解的限制。这些研究将促进基于SL 0101药效团的RSK抑制剂作为抗癌化疗剂的开发。(c)2007爱思唯尔有限公司保留所有权利。
Inappropriate activity of p90 ribosomal S6 kinase (RSK) has been implicated in various human cancers as well as other pathologies. We previously reported the isolation, characterization, and synthesis of the natural product kaempferol 3-O-(3 '',4 ''-di-O-acetyl-alpha-L-rhamnopyranoside), termed SL0101 [Smith, J. A.; Poteet-Smith, C. E.; Xu, Y.; Errington, T. M.; Hecht, S. M.; Lannigan, D. A. Cancer Res., 2005, 65, 1027-1034: Xu, Y.-M; Smith, J. A.; Lannigan, D. A.; Hecht, S. M. Bioorg. Med. Chem., 2006, 14, 3974-3977: Maloney, D. J.; Hecht, S. M. Org. Lett., 2005, 7, 1097-1099]. SL0101 is a potent and specific inhibitor of RSK; therefore, we performed an analysis of the structural basis for the inhibitory activity of this lead compound. In in vitro kinase assays we found that acylation of the rhamnose moiety and the 4', 5, and 7-hydroxyl groups are responsible for maintaining a high affinity interaction of RSK with SL0101. It is likely that the hydroxyl groups facilitate RSK binding through their ability to form hydrogen bonds. To determine whether the SL0101 derivatives were specific for inhibition of RSK we analyzed their ability to preferentially inhibit the growth of the human breast cancer line, MCF-7, compared to the normal human breast line, MCF-10A. We have previously validated this differential growth assay as a convenient readout for analyzing the specificity of RSK inhibitors [Smith, J. A.; Maloney, D. J.; Clark, D. E.; Xu, Y.-M.; Hecht, S. M.; Lannigan, D. A. Bioorg. Med Chem., 2006,14,6034-6042]. We found that acylation of the rhamnose moiety was essential for maintaining the selectivity for RSK inhibition in intact cells. Further, the efficacy of SL0101 in intact cells is limited by cellular uptake as well as possible hydrolysis of the acetyl groups on the rhamnose moiety by ubiquitous intracellular esterases. These studies should facilitate the development of a RSK inhibitor, based on the SL0101 pharmacophore, as an anti-cancer chemotherapeutic agent. (c) 2007 Elsevier Ltd. All rights reserved.