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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts
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Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts

机译：口服可利用的转录因子Stat3的小分子抑制剂使人乳腺癌和肺癌异种移植退化

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摘要

Computer-aided lead optimization derives a unique, orally bioavailable inhibitor of the signal transducer and activator of transcription (Stat)3 Src homology 2 domain. BP-1-102 binds Stat3 with an affinity (K_D) of 504 nM, blocks Stat3-phospho-tyrosine (pTyr) peptide interactions and Stat3 activation at 4-6.8 (μM, and selectively inhibits growth, survival, migration, and invasion of Stat3-dependent tumor cells. BP-1-102-mediated inhibition of aberrantly active Stat3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, VEGF, and Kriippel-like factor 8, which is identified as a Stat3 target gene that promotes Stat3-mediated breast tumor cell migration and invasion. Treatment of breast cancer cells with BP-1-102 further blocks Stat3-NF-kB cross-talk, the release of gran-ulocyte colony-stimulating factor, soluble intercellular adhesion molecule 1, macrophage migration-inhibitory factor/glycosylation-inhibiting factor, interleukin 1 receptor antagonist, and serine protease inhibitor protein 1, and the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral gavage delivery of BP-1-102 furnishes micro-molar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts.
机译：计算机辅助的导联优化可得到信号转导和转录激活子（Stat）3 Src同源2域的独特的，口服生物利用的抑制剂。 BP-1-102以504 nM的亲和力（K_D）结合Stat3，以4-6.8（μM）阻断Stat3-磷酸-酪氨酸（pTyr）肽相互作用和Stat3活化，并选择性地抑制Stat3的生长，存活，迁移和侵袭Stat3依赖性肿瘤细胞。BP-1-102介导的对肿瘤细胞中异常活跃Stat3的抑制作用抑制了c-Myc，Cyclin D1，Bcl-xL，Survivin，VEGF和Kriippel样因子8的表达。作为促进Stat3介导的乳腺癌细胞迁移和侵袭的Stat3靶基因，用​​BP-1-102处理乳腺癌细胞可进一步阻止Stat3-NF-kB串扰，释放粒细胞集落刺激因子，可溶性细胞间粘附分子1，巨噬细胞迁移抑制因子/糖基化抑制因子，白介素1受体拮抗剂和丝氨酸蛋白酶抑制剂蛋白1以及粘着斑激酶和paxillin的磷酸化，同时增强E-cadherin的表达。交货BP-1-102可以在肿瘤组织中提供微摩尔或微克水平，并抑制人乳腺癌和肺肿瘤异种移植物的生长。

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    Xiaolei Zhang; Peibin Yue; Brent D.G.Page; Tianshu Li; Wei Zhao; Andrew T.Namanja; David Paladino; Jihe Zhao; Yuan Chen; Patrick T.Gunning; James Turkson;

  • 作者单位

    Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827;

    Cancer Biology and Experimental Therapeutics Programs, University of Hawaii Cancer Center, Honolulu, HI 96813;

    Department of Chemistry, University of Toronto at Mississauga, Mississauga, ON, Canada,L5L 1C6;

    Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827;

    Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827;

    Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010;

    Cancer Biology and Experimental Therapeutics Programs, University of Hawaii Cancer Center, Honolulu, HI 96813;

    Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827;

    Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010;

    Department of Chemistry, University of Toronto at Mississauga, Mississauga, ON, Canada,L5L 1C6;

    Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827,Cancer Biology and Experimental Therapeutics Programs, University of Hawaii Cancer Center, Honolulu, HI 96813;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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