Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription.
Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription.
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DOI：
10.1016/j.bmc.2012.09.056
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发表时间：
2012-12-01
影响因子：
3.5
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Li BX;Yamanaka K;Xiao X
CREB(cAMP反应元件结合蛋白)是受体酪氨酸激酶或G蛋白偶联受体等多种信号通路的下游转录因子。CREB只有在Ser133处被磷酸化，并通过CREB中的KID结构域(KID)和CBP中的KID结构域与CREB结合蛋白(CBP)结合后，CREB才被激活。不同器官的肿瘤组织中CREB的表达和活化水平较高。因此，CREB被认为是一种很有前途的抗癌药物靶点。我们先前描述了萘酚AS-E(1a)是活细胞中CREB介导的基因转录的小分子抑制物。在这里，我们报道了通过修饰附加苯环来研究1a的构效关系。体外抑制KIX-KID相互作用，细胞抑制CREB介导的基因转录，抑制四种癌细胞株(A549、MCF-7、MDA-MB-231和MDA-MB-468)的增殖。SAR显示，在抑制KIX-KID相互作用的对位，首选的是一个小的电子撤除基团。选择化合物1a进行进一步的生物学鉴定，发现1a下调了内源CREB靶基因的表达。CREB突变体VP16-CREB在MCF-7细胞中的表达使细胞对1a产生抗性，表明CREB在介导其抗癌活性中起关键作用。此外，1a对正常人体细胞没有毒性。总体而言，这些数据支持1a代表了进一步发展为具有新作用机制的潜在癌症疗法的结构模板。
CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure–activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX–KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX–KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action.
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影响因子：
3.2
作者：
Li, Bingbing X.;Xiao, Xiangshu
通讯作者：
Xiao, Xiangshu
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
7.3
作者：
Jiang, Min;Li, Bingbing X.;Xie, Fuchun;Delaney, Frances;Xiao, Xiangshu
通讯作者：
Xiao, Xiangshu
DOI：
10.1073/pnas.91.12.5647
发表时间：
1994-06-07
影响因子：
11.1
作者：
HUMMLER, E;COLE, TJ;SCHUTZ, G
通讯作者：
SCHUTZ, G
影响因子：
64.5
作者：
Radhakrishnan, I;PerezAlvarado, GC;Wright, PE
通讯作者：
Wright, PE