Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, United States.
J Med Chem. 2011 May 26;54(10):3549-63. doi: 10.1021/jm2000882. Epub 2011 Apr 26.
Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure-activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the β-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing β-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1 μM in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.
信号转导子和转录激活子 3（Stat3）是抗癌药物设计的靶点，通过其 SH2 结构域与生长因子和细胞因子受体上的磷酸酪氨酸残基募集而被激活。我们在此报告针对 Stat3 的 SH2 结构域的磷酸肽模拟物的构效关系研究。在 pTyr 模拟物 4-磷酸肉桂酰胺的β-位上包含一个甲基，可使亲和力增强 2-3 倍。含有β-甲基肉桂酰胺、二肽支架 Haic 和 Nle-cis-3,4-甲烷脯氨酸以及谷氨酰胺替代物的双-特戊酰氧甲基前药在各种癌细胞系中具有很高的效力，在 0.5-1μM 时完全抑制 Stat3 Tyr705 的磷酸化。抑制剂对 Stat3 相对于 Stat1、Stat5、Src 和 p85 的 PI3K 具有选择性，表明能够在完整细胞中区分各个 SH2 结构域。在完全抑制 Stat3 磷酸化的浓度下，前药对一组肿瘤细胞没有细胞毒性，从而在细胞毒性和激活 Stat3 下游的作用之间清楚地区分。
