Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones
Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones
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DOI：
10.1016/j.bmc.2014.04.032
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发表时间：
2014-06-15
影响因子：
3.5
通讯作者：
Shuto, Satoshi
中科院分区：
文献类型：
--
作者：
Kawamura, Shuhei;Unno, Yuka;Shuto, Satoshi
蛋白酶体抑制剂是目前越来越关注的抗癌候选药物的焦点。我们最近对肽天然产物belactosin A进行了系统的构效关系研究，并确定了非肽衍生物2是一种高效的蛋白酶体抑制剂。然而，2的细胞生长抑制作用仅为中等，可能是由于生物不稳定的β -内酯战斗部。肽环氧酮是一类重要的蛋白酶体抑制剂，在细胞系统中表现出高效的α， β -环氧酮战斗部。重要的是，乳肽素衍生物主要与蛋白酶体的引物结合位点结合，而肽环氧酮仅与蛋白酶体的非引物结合位点结合，这表明它们的杂交可能导致一类新的蛋白酶体抑制剂的开发。因此，我们通过合理的结构设计成功鉴定了一种新的蛋白酶体抑制剂3和4的化学型，它们有望结合蛋白酶体的引物和非引物结合位点。(C) 2014 Elsevier Ltd.版权所有。
Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure-activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable beta-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient alpha,beta-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome. (C) 2014 Elsevier Ltd. All rights reserved.