A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes.
A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes.
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DOI：
10.1016/j.bcp.2010.01.001
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发表时间：
2010-05-15
影响因子：
5.8
通讯作者：
Turkson, James
中科院分区：
文献类型：
--
作者：
Zhang, Xiaolei;Yue, Peibin;Fletcher, Steven;Zhao, Wei;Gunning, Patrick T.;Turkson, James
对STAT3：STAT3二聚中磷酸酪氨酸(PTyr)-SH2结构域相互作用的分子建模，结合STAT3二聚干扰物S3I-201的电子结构分析，提供了一组不同的类似物。我们从体外生化和生物物理研究中发现，结构类似物S3I-201.1066直接与STAT3或SH2结构域相互作用，亲和力(Kd)为2.74 nM，并破坏STAT3与同源pTyr肽GpYLPQTV-NH2的结合，IC50值为23μM。此外，S3I-201.1066选择性地阻断STAT3与表皮生长因子受体(EGFR)的结合，并抑制EGF刺激的小鼠成纤维细胞中STAT3的酪氨酸磷酸化和核转位。在具有异常STAT3活性的癌细胞中，S3I-201.1066抑制构成的STAT3DNA结合和转录活性。相反，S3I-201.1066对Src的激活或EGFR介导的ERK1/2MAPK通路的激活没有影响。S3I-201.1066选择性地抑制人乳腺癌和胰腺癌细胞系以及携带持续活性STAT3的v-Src转化的小鼠成纤维细胞的存活、存活和恶变。S3I-201.1066可下调c-Myc、Bclxl、Survivin、基质金属蛋白酶9和血管内皮生长因子的表达。体内给药S3I-201.1066在小鼠人乳腺癌模型中诱导了显著的抗肿瘤反应，这与抑制构成活性的STAT3和抑制已知的STAT3调节基因有关。我们的研究发现了一种新的小分子，它与STAT3高亲和力结合，阻断STAT3的激活和功能，从而在携带持续活性的STAT3的人乳腺肿瘤移植瘤中诱导抗肿瘤反应。
The molecular modeling of the phosphotyrosine (pTyr)-SH2 domain interaction in the Stat3:Stat3 dimerization, combined with in silico structural analysis of the Stat3 dimerization disruptor, S3I-201, has furnished a diverse set of analogs. We present evidence from in vitro biochemical and biophysical studies that the structural analog, S3I-201.1066 directly interacts with Stat3 or the SH2 domain, with an affinity (KD) of 2.74 nM, and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH2, with an IC50 of 23 μM. Moreover, S3I-201.1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201.1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities. By contrast, S3I-201.1066 has no effect on Src activation or the EGFR-mediated activation of the Erk1/2MAPK pathway. S3I-201.1066 selectively suppresses the viability, survival, and malignant transformation of the human breast and pancreatic cancer lines and the v-Src-transformed mouse fibroblasts harboring persistently-active Stat3. Treatment with S3I-201.1066 of malignant cells harboring aberrantly-active Stat3 down-regulated the expression of c-Myc, Bcl-xL, Survivin, the matrix metalloproteinase 9, and VEGF. The in vivo administration of S3I-201.1066 induced significant antitumor response in mouse models of human breast cancer, which correlates with the inhibition of constitutively-active Stat3 and the suppression of known Stat3-regulated genes. Our studies identify a novel small-molecule that binds with a high affinity to Stat3, blocks Stat3 activation and function, and thereby induces antitumor response in human breast tumor xenografts harboring persistently-active Stat3.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
7.3
作者：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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