Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy.
Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy.
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DOI：
10.1016/j.ejmech.2013.01.023
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发表时间：
2013-04
影响因子：
6.7
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Chen, Haijun;Yang, Zhengduo;Ding, Chunyong;Chu, Lili;Zhang, Yusong;Terry, Kristin;Liu, Huiling;Shen, Qiang;Zhou, Jia
基于片段的药物设计（FBDD）是一种很有前途的方法，用于产生具有增强活性的铅分子，特别是针对治疗靶点的药物样特性。在此，我们报道了基于片段的药物设计，系统的化学合成和药理学评价，利用已知STAT3抑制剂的六个特殊片段，新型支架作为有效的抗癌药物。一些新的分子，如化合物5、12和19，可能作为先进的化学先导物被发现。最有效的化合物5 （HJC0123）在低微摩尔至纳摩尔IC50值的乳腺癌和胰腺癌细胞中抑制STAT3启动子活性，下调STAT3磷酸化，增加cleaved caspase-3的表达，抑制细胞周期进程，促进细胞凋亡。此外，化合物5显著抑制雌激素受体（ER）阴性乳腺癌MDA-MB-231异种移植物肿瘤的体内生长（p.o），表明其作为一种有效的口服生物利用度的人类癌症治疗候选药物的巨大潜力。
Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy.
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影响因子：
7.3
作者：
Debnath, Bikash;Xu, Shili;Neamati, Nouri
通讯作者：
Neamati, Nouri
影响因子：
15.9
作者：
Bromberg, J
通讯作者：
Bromberg, J
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE
DOI：
10.1109/access.2023.3293001
发表时间：
--
期刊：
IEEE Access
影响因子：
3.6
作者：
Yi-Ming Tseng; Bang-Ren Chen; Wei-Cheng Lin; Wen-Jay Lee; Nan-Yow Chen; Tian-Li Wu
通讯作者：
Yi-Ming Tseng
影响因子：
64.5
作者：
Bromberg, JF;Wrzeszczynska, MH;Darnell, JE
通讯作者：
Darnell, JE