A Novel Tamoxifen Derivative, Ridaifen-F, Is a Nonpeptidic Small-molecule Proteasome Inhibitor
A Novel Tamoxifen Derivative, Ridaifen-F, Is a Nonpeptidic Small-molecule Proteasome Inhibitor
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新型他莫昔芬衍生物 Ridaifen-F 是一种非肽小分子蛋白酶体抑制剂
DOI：
10.1016/j.ejmech.2013.11.009
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发表时间：
2014
影响因子：
6.7
通讯作者：
Tamio Mizukami
中科院分区：
文献类型：
--
作者：
Makoto Hasegawa;Yukari Yasuda;Makoto Tanaka;Kenya Nakata;Eri Umeda;Yanwen Wang;Chihiro Watanabe;Shoko Uetake,Tatsuki Kunoh;Masafumi Shionyu;Ryuzo Sasaki;Isamu Shiina;Tamio Mizukami
在对人类20S蛋白酶体的非肽非共价抑制剂的调查中，我们发现一种新的他莫昔芬衍生物RID-F（化合物6）在亚微摩尔水平上抑制了蛋白酶体的所有三种蛋白酶活性。构效关系研究表明，RID-F类似物（RID-F- s *4, compound25）是能抑制蛋白酶体活性的最小衍生物化合物，其效价与RID-F相似。生物素-乳蛋白A（一种蛋白酶体抑制剂）结合的抑制模式动力学分析和竞争实验表明，RID-F衍生物以不同的方式与蛋白酶亚基相互作用。用这些化合物培养人类细胞可导致泛素化蛋白的积累和细胞凋亡的诱导。因此，RID-F衍生物可能是产生一类新的蛋白酶体抑制剂的有用的铅化学品。
In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure–activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors.