An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation.
An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation.
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作者：
我们设计并合成了一系列新型的萘醌衍生物，其中萘醌类化合物具有很高的抑制肿瘤细胞生长的活性，且毒性较低。我们确定了BMWW通过靶向STAT 3抑制三阴性乳腺癌细胞活性，并为TNBC临床药物开发提供了新的化合物结构候选物。背景资料：三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，五年生存期比其他乳腺癌亚型短，并且缺乏靶向和激素治疗策略。信号转导和转录激活因子3（STAT 3）信号传导在包括TNBC在内的各种肿瘤中上调，并且在调节多种增殖和凋亡相关基因的表达中起着至关重要的作用。结果如下：通过将天然化合物STA-21和Aulosirazole的独特结构与抗肿瘤活性相结合，我们合成了一类新型异恶唑醌衍生物，并表明其中一种化合物ZSW与STAT 3的SH 2结构域结合，导致STAT 3表达降低。TNBC细胞中的激活。此外，BMWW促进STAT 3泛素化，在体外抑制TNBC细胞的增殖，并在体内以可管理的毒性减弱肿瘤生长。BMWW还通过抑制STAT 3减少乳腺癌干细胞（BCSC）的乳腺球形成。结论：我们的结论是，新的异恶唑啉醌CNOW可能被开发为癌症治疗，因为它的目标是STAT 3，从而抑制癌细胞的干细胞。
We designed and synthesized a series of novel naphthoquinone derivatives, of which ZSW has a high activity to inhibit the growth of tumor cells and low toxicity. We determined that ZSW suppresses triple-negative breast cancer cell activity by targeting STAT3 and provides a new compound structure candidate for TNBC clinical drug development. Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. Results: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. Conclusions: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells.
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影响因子：
5.7
作者：
Kitamura H;Ohno Y;Toyoshima Y;Ohtake J;Homma S;Kawamura H;Takahashi N;Taketomi A
通讯作者：
Taketomi A
影响因子：
45.3
作者：
Gruenwald, Viktor;Karch, Annika;Kunitz, Annegret
通讯作者：
Kunitz, Annegret
影响因子：
50.3
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
影响因子：
6.4
作者：
Banerjee K;Resat H
通讯作者：
Resat H
DOI：
10.1016/s2352-3026(21)00270-2
发表时间：
2021-12
期刊：
The Lancet. Haematology
影响因子：
--
作者：
Kantarjian H;Short NJ;DiNardo C;Stein EM;Daver N;Perl AE;Wang ES;Wei A;Tallman M
通讯作者：
Tallman M