Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth.
Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth.
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DOI：
10.1038/s41388-017-0076-0
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发表时间：
2018-05
期刊：
影响因子：
8
通讯作者：
Zhang JT
中科院分区：
文献类型：
--
作者：
Li X;Ma H;Li L;Chen Y;Sun X;Dong Z;Liu JY;Zhu W;Zhang JT
信号换能器和转录激活因子3 （STAT3）在恶性肿瘤中构成性激活，在肿瘤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一种有吸引力的策略。双吲哚马来酰亚胺生物碱（BMA）已被证明具有抗癌活性，并被认为通过抑制蛋白激酶c来抑制肿瘤细胞的生长。在本研究中，我们发现新合成的BMA类似物BMA097可有效抑制肿瘤细胞和异种移植物的生长并诱导自发凋亡。我们还提供证据表明，BMA097直接结合STAT3的SH2结构域，抑制STAT3的磷酸化和激活，导致STAT3下游靶基因的表达减少。构效关系分析表明，2,5-二氢吡咯-2,5-二酮中的羟基甲基抑制了BMA类似物的stat3抑制活性。综上所述，我们认为合成的BMA类似物可能通过靶向并结合STAT3的SH2结构域并抑制STAT3信号通路而被开发为抗癌药物。
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 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 analogue, 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 analogues. Together, we conclude that the synthetic BMA analogues may be developed as anticancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway.
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影响因子：
4
作者：
Huang, Wei;Dong, Zizheng;Wang, Fang;Peng, Hui;Liu, Jing-Yuan;Zhang, Jian-Ting
通讯作者：
Zhang, Jian-Ting
DOI：
10.1073/pnas.0404100101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Dechow, TN;Pedranzini, L;Bromberg, JF
通讯作者：
Bromberg, JF
影响因子：
11.2
作者：
Li, Yuan;Du, Hong;Yan, Cong
通讯作者：
Yan, Cong
影响因子：
4
作者：
Gartsbein, M;Alt, A;Tennenbaum, T
通讯作者：
Tennenbaum, T
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE