鉴定 Stat3 SH2 结构域的非磷酸化、细胞通透的小分子配体。
Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.
机构信息
Department of Chemistry, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, Canada L5L 1C6.
出版信息
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5605-9. doi: 10.1016/j.bmcl.2011.06.056. Epub 2011 Jun 30.
Abstract
Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 μM), inhibited Stat3-Stat3 protein interactions (IC(50)=19 μM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 μM, respectively).
摘要
信号转导子和转录激活子 3（Stat3）蛋白是一种细胞浆转录因子，在许多人类癌症中异常激活。已经表明，激活的 Stat3-Stat3 蛋白复合物抑制剂在治疗携带激活的 Stat3 的人类癌症方面具有治疗潜力。在此，我们报告了一个包含 Stat3 SH2 结构域结合物的水杨酸的聚焦文库的设计和合成。最有效的抑制剂 17o，有效地破坏了 Stat3-磷酸肽复合物（K(i)=13 μM），抑制了 Stat3-Stat3 蛋白相互作用（IC(50)=19 μM），并沉默了细胞内 Stat3 磷酸化和 Stat3-靶基因表达谱。Stat3 功能的抑制在乳腺癌和多发性骨髓瘤（MM）肿瘤细胞中与诱导的细胞死亡相关（EC(50)=10 和 16 μM，分别）。
相似文献
1
Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.鉴定 Stat3 SH2 结构域的非磷酸化、细胞通透的小分子配体。
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5605-9. doi: 10.1016/j.bmcl.2011.06.056. Epub 2011 Jun 30.
2
Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules.用基于水杨酸的小分子拮抗 Stat3-Stat3 二聚体。
ChemMedChem. 2011 Aug 1;6(8):1459-70. doi: 10.1002/cmdc.201100194. Epub 2011 May 25.
3
Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain.鉴定新型紫草素衍生物作为靶向 STAT3 SH2 结构域的抗肿瘤药物。
Sci Rep. 2017 Jun 6;7(1):2863. doi: 10.1038/s41598-017-02671-7.
4
Design, synthesis and activity of novel 2,6-disubstituted purine derivatives, potential small molecule inhibitors of signal transducer and activator of transcription 3.新型 2,6-二取代嘌呤衍生物的设计、合成及活性研究，有望成为信号转导和转录激活因子 3 的小分子抑制剂。
Eur J Med Chem. 2019 Oct 1;179:218-232. doi: 10.1016/j.ejmech.2019.06.017. Epub 2019 Jun 21.
5
A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro.一种细胞通透型 Stat3 SH2 结构域模拟物可抑制 Stat3 激活并在体外诱导抗肿瘤细胞效应。
J Biol Chem. 2010 Nov 12;285(46):35855-65. doi: 10.1074/jbc.M110.154088. Epub 2010 Aug 31.
6
Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma.用四足小分子Src 同源结构域结合物抑制异常信号转导和转录激活蛋白的激活：针对多发性骨髓瘤的有前途的药物。
J Med Chem. 2013 Sep 26;56(18):7190-200. doi: 10.1021/jm3017255. Epub 2013 Sep 13.
7
Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.小分子 STAT5-SH2 结构域抑制剂具有很强的抗白血病活性。
J Med Chem. 2012 Feb 9;55(3):1047-55. doi: 10.1021/jm200720n. Epub 2012 Jan 13.
8
Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.通过基于计算机的定向片段药物设计发现新型 STAT3 小分子抑制剂。
J Med Chem. 2013 Jun 13;56(11):4402-12. doi: 10.1021/jm400080c. Epub 2013 May 16.
9
Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.基于苯并噻唑的衍生物作为有效的信号转导子和转录激活子 3（STAT3）信号通路抑制剂的合理药物设计。
Eur J Med Chem. 2021 Apr 15;216:113333. doi: 10.1016/j.ejmech.2021.113333. Epub 2021 Mar 2.
10
Discovery, synthesis, and evaluation of small-molecule signal transducer and activator of transcription 3 inhibitors.小分子信号转导子与转录激活子3抑制剂的发现、合成及评估
Chem Pharm Bull (Tokyo). 2012;60(12):1574-80. doi: 10.1248/cpb.c12-00745.
引用本文的文献
1
STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges.STAT 家族转录因子在乳腺癌中的作用：发病机制及治疗的机遇与挑战。
Semin Cancer Biol. 2022 Nov;86(Pt 3):84-106. doi: 10.1016/j.semcancer.2022.08.003. Epub 2022 Aug 19.
2
Histone H1.2 promotes hepatocarcinogenesis by regulating signal transducer and activator of transcription 3 signaling.组蛋白 H1.2 通过调节信号转导子和转录激活子 3 信号促进肝癌发生。
Cancer Sci. 2022 May;113(5):1679-1692. doi: 10.1111/cas.15336. Epub 2022 Mar 30.
3
Design, synthesis, and evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition.设计、合成及评估 STAT3 抑制作用的 BP-1-102 类似物，这些类似物的疏水片段经过了修饰。
J Enzyme Inhib Med Chem. 2021 Dec;36(1):410-424. doi: 10.1080/14756366.2020.1871336.
4
Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model.小胶质细胞与患者来源的神经胶质瘤细胞之间的串扰在三维明胶水凝胶模型中抑制侵袭。
J Neuroinflammation. 2020 Nov 18;17(1):346. doi: 10.1186/s12974-020-02026-6.
5
Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic-inorganic inhibitors.靶向 STAT3 抗凋亡途径的有机和杂化有机-无机抑制剂。
Org Biomol Chem. 2020 May 6;18(17):3288-3296. doi: 10.1039/c9ob02682g.
6
Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death.不可逆的 TrxR1 抑制剂阻断 STAT3 活性并诱导癌细胞死亡。
Sci Adv. 2020 Mar 20;6(12):eaax7945. doi: 10.1126/sciadv.aax7945. eCollection 2020 Mar.
7
Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers.造血系统癌症中致癌性 STAT3 和 STAT5 信号通路的药理学抑制作用
Cancers (Basel). 2020 Jan 18;12(1):240. doi: 10.3390/cancers12010240.
8
Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens.透明质酸功能化明胶水凝胶揭示细胞外基质信号调节厄洛替尼对患者来源的胶质母细胞瘤标本的疗效。
Biomaterials. 2019 Oct;219:119371. doi: 10.1016/j.biomaterials.2019.119371. Epub 2019 Jul 19.
9
BP‑1‑102 exerts an antitumor effect on the AGS human gastric cancer cell line through modulating the STAT3 and MAPK signaling pathways.BP-1-102 通过调节 STAT3 和 MAPK 信号通路对 AGS 人胃癌细胞系发挥抗肿瘤作用。
Mol Med Rep. 2019 Apr;19(4):2698-2706. doi: 10.3892/mmr.2019.9892. Epub 2019 Jan 24.
10
Evaluation of quantitative assays for the identification of direct signal transducer and activator of transcription 3 (STAT3) inhibitors.用于鉴定直接信号转导和转录激活因子3（STAT3）抑制剂的定量分析方法的评估
Oncotarget. 2016 Nov 22;7(47):77998-78008. doi: 10.18632/oncotarget.12868.
本文引用的文献
1
Identification of a New Series of STAT3 Inhibitors by Virtual Screening.通过虚拟筛选鉴定一系列新型STAT3抑制剂
ACS Med Chem Lett. 2010 Jul 13;1(8):371-5. doi: 10.1021/ml1000273. eCollection 2010 Nov 11.
2
Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules.用基于水杨酸的小分子拮抗 Stat3-Stat3 二聚体。
ChemMedChem. 2011 Aug 1;6(8):1459-70. doi: 10.1002/cmdc.201100194. Epub 2011 May 25.
3
Signal transducer and activator of transcription 3 inhibitors: a patent review.信号转导和转录激活因子 3 抑制剂：专利研究综述。
Expert Opin Ther Pat. 2011 Jan;21(1):65-83. doi: 10.1517/13543776.2011.539205. Epub 2010 Nov 29.
4
Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches.定义 JAK-STAT 通路在头颈部和胸部恶性肿瘤中的作用：对未来治疗方法的影响。
Drug Resist Updat. 2010 Jun;13(3):67-78. doi: 10.1016/j.drup.2010.04.001. Epub 2010 May 14.
5
A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes.一种新型小分子破坏 Stat3 SH2 结构域-磷酸酪氨酸相互作用和 Stat3 依赖性肿瘤过程。
Biochem Pharmacol. 2010 May 15;79(10):1398-409. doi: 10.1016/j.bcp.2010.01.001. Epub 2010 Jan 11.
6
Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein.分子破坏致癌信号转导子和转录激活子 3（STAT3）蛋白。
Biochem Cell Biol. 2009 Dec;87(6):825-33. doi: 10.1139/o09-044.
7
Disruption of transcriptionally active Stat3 dimers with non-phosphorylated, salicylic acid-based small molecules: potent in vitro and tumor cell activities.用基于水杨酸的非磷酸化小分子破坏转录活性Stat3二聚体：强大的体外和肿瘤细胞活性。
Chembiochem. 2009 Aug 17;10(12):1959-64. doi: 10.1002/cbic.200900172.
8
Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation.抑制钠钾三磷酸腺苷酶泵可使癌细胞对失巢凋亡敏感，并防止远处肿瘤形成。
Cancer Res. 2009 Apr 1;69(7):2739-47. doi: 10.1158/0008-5472.CAN-08-2530. Epub 2009 Mar 17.
9
Chemical probes that competitively and selectively inhibit Stat3 activation.竞争性和选择性抑制Stat3激活的化学探针。
PLoS One. 2009;4(3):e4783. doi: 10.1371/journal.pone.0004783. Epub 2009 Mar 10.
10
Targeting protein-protein interactions: suppression of Stat3 dimerization with rationally designed small-molecule, nonpeptidic SH2 domain binders.靶向蛋白质-蛋白质相互作用：用合理设计的小分子非肽类SH2结构域结合剂抑制Stat3二聚化
Chembiochem. 2008 Nov 24;9(17):2800-3. doi: 10.1002/cbic.200800291.
Zotero 插件