CREB的全身抑制在体内具有良好的耐受性。,Scientific Reports

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CREB的全身抑制在体内具有良好的耐受性。
Scientific Reports ( IF 3.8 ) Pub Date : 2016-10-03 , DOI: 10.1038/srep34513
Bingbing X. Li , Ryan Gardner , Changhui Xue , David Z. Qian , Fuchun Xie , George Thomas , Steven C. Kazmierczak , Beth A. Habecker , Xiangshu Xiao

cAMP反应元件结合蛋白（CREB）是一种由多种细胞外信号（包括生长因子和激素）激活的核转录因子。这些细胞外信号通过各种蛋白丝氨酸/苏氨酸激酶在Ser133处的磷酸化激活CREB。一旦被磷酸化，它会促进其与转录共激活因子CREB结合蛋白（CBP）及其旁系同源物p300的缔合，从而激活CREB依赖的基因转录。已经显示出不同来源的肿瘤组织呈现出CREB的过度表达和/或过度活化，表明CREB是潜在的癌症药物靶标。我们先前确定666-15是CREB的有效抑制剂，在体外和体内均具有有效的抗癌活性。本文中，我们研究了666-15的特异性，并评估了其潜在的体内毒性。我们发现666-15在抑制CREB方面具有相当高的选择性。还发现666-15易于生物利用以达到抑制CREB的药理学相关浓度。此外，用666-15处理的小鼠没有显示出体重，全血细胞计数，血液化学特征，心脏收缩力和肝脏，肾脏和心脏组织组织学变化的证据。这些结果首次证明了CREB的药理抑制作用在体内具有良好的耐受性，并表明此类抑制剂应成为有前途的癌症治疗剂。肝脏，肾脏和心脏的血液化学概况，心脏收缩力和组织组织学。这些结果首次证明了CREB的药理抑制作用在体内具有良好的耐受性，并表明此类抑制剂应成为有前途的癌症治疗剂。肝脏，肾脏和心脏的血液化学概况，心脏收缩力和组织组织学。这些结果首次证明了CREB的药理学抑制作用在体内具有良好的耐受性，并表明此类抑制剂应成为有前途的癌症治疗剂。

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Systemic Inhibition of CREB is Well-tolerated in vivo.

cAMP-response element binding protein (CREB) is a nuclear transcription factor activated by multiple extracellular signals including growth factors and hormones. These extracellular cues activate CREB through phosphorylation at Ser133 by various protein serine/threonine kinases. Once phosphorylated, it promotes its association with transcription coactivators CREB-binding protein (CBP) and its paralog p300 to activate CREB-dependent gene transcription. Tumor tissues of different origins have been shown to present overexpression and/or overactivation of CREB, indicating CREB as a potential cancer drug target. We previously identified 666-15 as a potent inhibitor of CREB with efficacious anti-cancer activity both in vitro and in vivo. Herein, we investigated the specificity of 666-15 and evaluated its potential in vivo toxicity. We found that 666-15 was fairly selective in inhibiting CREB. 666-15 was also found to be readily bioavailable to achieve pharmacologically relevant concentrations for CREB inhibition. Furthermore, the mice treated with 666-15 showed no evidence of changes in body weight, complete blood count, blood chemistry profile, cardiac contractility and tissue histologies from liver, kidney and heart. For the first time, these results demonstrate that pharmacological inhibition of CREB is well-tolerated in vivo and indicate that such inhibitors should be promising cancer therapeutics.

更新日期：2016-10-05

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