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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth
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NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth

机译：无释放的STAT3抑制剂抑制BRAF-突变体黑素瘤生长

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摘要

Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazoleioxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of similar to 0.5 mu M. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naive (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：STAT3的组成性激活能起到黑色素瘤的发展具有重要作用。 STAT3靶向治疗报告，以显示黑色素瘤窝藏BRAFV600E突变，也耐威罗菲尼，黑色素瘤的疗效。我们设计并合成了一系列取代的一氧化氮（NO） - 脱模剂喹诺酮-1,2,4- triazoleioxime混合动力车，假设到，引入一个STAT3结合支架的将提高它们的细胞毒性的。所有测试的杂种表现出体外NO产生的水平相当。 7b和7c显示出直接结合于具有相似IC 50的STAT3-SH域到0.5亩M.而且，它们废除STAT3酪氨酸磷酸化在几种癌细胞系，包括携带BRAFV600E突变的A375黑色素瘤细胞系。与此同时，他们也没有影响到上游激酶或其他STAT亚型的磷酸化。图7c抑制在小鼠胚胎成纤维STAT3核转位而7b和7c抑制在A375细胞系中STAT3的DNA结合活性。他们的抗增殖活性归因于其触发产生活性氧和诱导的A375细胞系G1期细胞周期停滞的能力。有趣的是，7b和7c显示稳健的细胞生长的抑制和以两对BRAF抑制剂幼稚（-S）和含有BRAF V600E突变抗性（-R）黑色素瘤细胞系的细胞凋亡诱导。令人惊讶地，已知MEL1617-R细胞是MEK抑制由GSK1120212更多的阻力比MEL1617-S细胞表现出对7b和7c类似的反应。 （c）2019年Elsevier Masson SAS。版权所有。

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