A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis.
A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis.
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发表时间：
2012
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通讯作者：
E. Auzenne;J. Klostergaard;P. Mandal;W. Liao;Zhen Lu;Fengqin Gao;R. Bast;F. Robertson;J. McMurray
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作者：
E. Auzenne;J. Klostergaard;P. Mandal;W. Liao;Zhen Lu;Fengqin Gao;R. Bast;F. Robertson;J. McMurray
信号转导器和转录激活剂 3 (Stat3) 在许多人类癌症和癌细胞系中被组成型激活。通过其 Src 同源 2 (SH2) 结构域，Stat3 被募集至细胞因子和生长因子受体胞内结构域上的磷酸酪氨酸残基，随后在 Tyr705 上磷酸化、二聚化、易位至细胞核，据报道参与与血管生成、转移、生长和存活相关的基因的表达。为了阻断这一过程，我们正在开发细胞渗透性、磷酸酶稳定的磷酸肽模拟物，靶向 Stat3 的 SH2 结构域，抑制培养肿瘤细胞中 Stat3 的 Tyr705 的磷酸化（Mandal 等人，J. Med. Chem. 54, 3549-5463, 2011）。在抑制酪氨酸磷酸化的浓度下，这些材料没有细胞毒性，类似于最近关于 JAK 抑制剂的报道。在较高浓度下，细胞毒性伴随着脱靶效应。我们报告说，用肽模拟物 PM-73G 治疗小鼠 MDA-MB-468 人乳腺癌异种移植物可显着抑制肿瘤生长，同时伴随着 VEGF 产生和微血管密度的减少。没有观察到细胞凋亡或经典基因细胞周期蛋白 D1 或存活蛋白表达变化的证据。因此，选择性抑制 Stat3 Tyr705 磷酸化可能是治疗癌症的一种新的抗血管生成策略。
Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a number of human cancers and cancer cell lines. Via its Src homology 2 (SH2) domain, Stat3 is recruited to phosphotyrosine residues on intracellular domains of cytokine and growth factor receptors, whereupon it is phosphorylated on Tyr705, dimerizes, translocates to the nucleus and is reported to participate in the expression of genes related to angiogenesis, metastasis, growth and survival. To block this process, we are developing cell-permeable, phosphatase-stable phosphopeptide mimics, targeted to the SH2 domain of Stat3, that inhibit the phosphorylation of Tyr705 of Stat3 in cultured tumor cells (Mandal et al., J. Med. Chem. 54, 3549-5463, 2011). At concentrations that inhibit tyrosine phosphorylation, these materials were not cytotoxic, similar to recent reports on JAK inhibitors. At higher concentrations, cytotoxicity was accompanied by off-target effects. We report that treatment of MDA-MB-468 human breast cancer xenografts in mice with peptidomimetic PM-73G significantly inhibited tumor growth, which was accompanied by reduction in VEGF production and microvessel density. No evidence of apoptosis or changes in the expression of the canonical genes cyclin D1 or survivin were observed. Thus selective inhibition of Stat3 Tyr705 phosphorylation may be a novel anti-angiogenesis strategy for the treatment of cancer.