Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and plays important roles in multiple aspects of cancer aggressiveness. Thus, targeting STAT3 promises to be an attractive strategy for the treatment of advanced metastatic tumors. Bisindolylmaleimide alkaloid (BMA) has been shown to have anti-cancer activities and was thought to suppress tumor cell growth by inhibiting protein kinase C. In this study, we show that a newly synthesized BMA analog, BMA097, is effective in suppressing tumor cell and xenograft growth and in inducing spontaneous apoptosis. We also provide evidence that BMA097 binds directly to the SH2 domain of STAT3 and inhibits STAT3 phosphorylation and activation, leading to reduced expression of STAT3 downstream target genes. Structure activity relationship analysis revealed that the hydroxymethyl group in the 2,5-dihydropyrrole-2,5-dione prohibits STAT3 inhibitory activity of BMA analogs. Altogether, we conclude that the synthetic BMA analogs may be developed as anti-cancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway.

中文翻译：

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新型合成的bisindolylmaleimide生物碱通过与SH2结构域结合来抑制STAT3活化并抑制乳腺癌异种移植瘤的生长。

信号转导子和转录激活因子3（STAT3）在恶性肿瘤中被组成性激活，并在癌症侵袭性的多个方面发挥重要作用。因此，靶向STAT3有望成为治疗晚期转移性肿瘤的有吸引力的策略。Bisindolylmaleimide生物碱（BMA）已被证明具有抗癌活性，并被认为可以通过抑制蛋白激酶C抑制肿瘤细胞的生长。异种移植的生长并诱导自发凋亡。我们还提供证据表明BMA097直接与STAT3的SH2域结合并抑制STAT3磷酸化和激活，从而导致STAT3下游靶基因的表达降低。结构活性关系分析表明，2，5-二氢吡咯-2，5-二酮中的羟甲基阻止了BMA类似物的STAT3抑制活性。总之，我们得出结论，合成的BMA类似物可通过靶向并结合STAT3的SH2域并抑制STAT3信号通路而发展为抗癌药。