Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein.
Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein.
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DOI：
10.1016/j.bmc.2010.12.010
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Gunning PT
中科院分区：
文献类型：
--
作者：
Shahani VM;Yue P;Fletcher S;Sharmeen S;Sukhai MA;Luu DP;Zhang X;Sun H;Zhao W;Schimmer AD;Turkson J;Gunning PT
致癌信号转导子和转录激活子 3 (STAT3) 蛋白信号通路的异常激活与人类癌症有着广泛的关联。鉴于 STAT3 在恶性转化和肿瘤发生中的显着失调作用，人们付出了巨大的努力来发现 STAT3 特异性抑制剂作为化学探针，用于定义支持恶性表型的异常 STAT3 介导的分子事件。为了鉴定适合检测肿瘤细胞中 STAT3 信号传导的新型 STAT3 选择性抑制剂，我们通过将已知的 STAT3 抑制性肽模拟物 ISS610 与源自 ILR/gp-130 的高亲和力 STAT3 结合肽基序缀合，探索了混合分子的设计。在体外生物物理和生化研究中检查了几种杂合分子对 STAT3 的抑制效力。在体外 DNA 结合活性/电泳迁移率变动测定 (EMSA) 中，先导抑制剂 14aa 与 STAT3 强烈结合 (KD = 900 nM)，破坏 STAT3：磷酸肽复合物 (Ki = 5 μM) 并抑制 STAT3 活性。此外，先导 STAT3 抑制剂 14aa 在 v-Src 转化的小鼠成纤维细胞 (NIH3T3/v-Src) 中诱导了对组成型 STAT3 激活的时间依赖性抑制，在 NIH3T3/v-Src 处理后 6 小时内，组成型活性 STAT3 被抑制 80%。然而，STAT3 活性在细胞处理后 24 小时恢复，表明该化合物可能发生降解。结果进一步表明，用化合物14aa-OH（化合物14aa的非pTyr版本）处理可抑制NIH3T3/v-Src中的异常STAT3活性。化合物14aa和14aa-OH的作用伴随着细胞活力的中度丧失。
Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) protein signaling pathways has been extensively implicated in human cancers. Given STAT3’s prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (KD = 900 nM), disrupt STAT3:phosphopeptide complexes (Ki = 5 μM) and suppress STAT3 activity in in vitro DNA-binding activity/ electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80 % suppression of constitutively-active STAT3 at six hours following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 hours after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.
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影响因子：
2.7
作者：
Gunning, Patrick T.;Katt, William P.;Hamilton, Andrew D.
通讯作者：
Hamilton, Andrew D.
影响因子：
7.3
作者：
Coleman, DR;Ren, ZY;McMurray, JS
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McMurray, JS
影响因子：
5.2
作者：
Mandal PK;Liao WS;McMurray JS
通讯作者：
McMurray JS
影响因子：
6.4
作者：
LIEBER, M;MAZZETTA, J;TODARO, G
通讯作者：
TODARO, G
影响因子：
5.6
作者：
Jones, G;Willett, P;Taylor, R
通讯作者：
Taylor, R