Discovery of a small-molecule inhibitor of the KIX-KID interaction.
Discovery of a small-molecule inhibitor of the KIX-KID interaction.
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DOI：
10.1002/cbic.200900552
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发表时间：
2009-11-23
期刊：
影响因子：
3.2
通讯作者：
Xiao, Xiangshu
中科院分区：
文献类型：
--
作者：
Li, Bingbing X.;Xiao, Xiangshu
蛋白质-蛋白质相互作用对于将信号从细胞外空间传递到细胞核以及对于细胞-细胞通信是必不可少的。因此，靶向蛋白质-蛋白质相互作用的小分子是解剖给定蛋白质-蛋白质相互作用的生物学功能和许多不同人类疾病的潜在治疗的重要研究工具。[1]然而，通过小分子靶向蛋白质-蛋白质相互作用仍然是一个重大挑战。[1，2]环AMP反应元件（CRE）结合蛋白（CREB）属于含碱性亮氨酸拉链（bZIP）的转录因子的大家族。[3，4]它在Ser 133处被促分裂原和应激活化蛋白激酶磷酸化。[4]磷酸化CREB（p-CREB）然后通过CREB中的激酶诱导结构域（KID）和CBP中的KID相互作用（KIX）结构域结合哺乳动物转录共激活因子CREB结合蛋白（CBP）。[5]该结合事件将进一步募集其他转录机器至基因启动子以激活CREB依赖性基因转录。[4]最近的研究表明，CREB在许多不同类型的癌症中过表达，包括前列腺癌，[6]乳腺癌，[7]非小细胞肺癌，[8]和急性髓性白血病。[9]因此，CREB-CBP的小分子抑制剂是潜在的抗癌药物。在此，我们描述了我们通过使用新的海肾荧光素酶互补测定发现萘酚AS-E（1）作为KIX-KID相互作用的细胞渗透性小分子抑制剂。
Protein–protein interactions are essential for transmitting signals from extracellular space to cell nuclei and also for cell–cell communication. Small molecules that target protein–protein interactions, therefore, are great research tools for dissecting the biological functions of a given protein–protein interaction and potential therapeutics for many different human diseases.[1] However, targeting protein–protein interactions by small molecules remains a significant challenge.[1, 2]Cyclic-AMP response element (CRE) binding protein (CREB) belongs to a large family of basic leucine zipper (bZIP)-containing transcription factors.[3, 4] It is phosphorylated at Ser133 by mitogen-and stress-activated protein kinases.[4] The phosphorylated CREB (p-CREB) then binds the mammalian transcription coactivator, CREB-binding protein (CBP) via the kinase-inducible domain (KID) in CREB and the KID-interacting (KIX) domain in CBP.[5] This binding event will further recruit other transcriptional machinery to the gene promoter to activate CREB-dependent gene transcription.[4] Recent studies have revealed that CREB is overexpressed in many different types of cancers including prostate cancer,[6] breast cancer,[7] non-small-cell lung cancer,[8] and acute myeloid leukemia.[9] Therefore, small-molecule inhibitors of CREB–CBP are potential anticancer agents. Herein we describe our discovery of naphthol AS-E (1) as a cell-permeable small-molecule inhibitor of the KIX–KID interaction by using a novel Renilla luciferase complementation assay.
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影响因子：
16.2
作者：
Tao, X;Finkbeiner, S;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
64.5
作者：
Radhakrishnan, I;PerezAlvarado, GC;Wright, PE
通讯作者：
Wright, PE
影响因子：
4
作者：
Fan, Frank;Binkowski, Brock F.;Wood, Keith V.
通讯作者：
Wood, Keith V.
DOI：
10.1158/1078-0432.ccr-08-1137
发表时间：
2009-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Sakamoto KM;Frank DA
通讯作者：
Frank DA
影响因子：
7.4
作者：
Paulmurugan, R;Gambhir, SS
通讯作者：
Gambhir, SS