The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer
The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer
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DOI：
10.1016/j.ejmech.2017.04.039
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发表时间：
2017-07-28
影响因子：
6.7
通讯作者：
Chu, Yong
中科院分区：
文献类型：
--
作者：
Gao, Yang;Ye, De-Yong;Chu, Yong
糖原合成酶3β(GSK 3β)是一种高度保守的丝氨酸/苏氨酸激酶，其在肿瘤中的作用仍存在争议。累积证据支持GSK-3β抑制剂在体外能抑制卵巢癌的发展，为卵巢癌的治疗开辟了新的方向。在这里，我们报道了一系列新的取代苯并噻嗪酮类化合物作为GSK-3β的非ATP竞争性抑制剂。进一步的研究表明，它们中的大多数在体外对卵巢癌细胞株具有抗增殖活性。在A2780细胞株中，化合物20G诱导细胞凋亡，使细胞周期停滞于G1期，在BALB/C裸鼠模型中表现出中等的抑制作用。这些结果表明，化合物20G作为首次报道的GSK-3β的非ATP竞争性小分子抑制剂，在体内外对卵巢癌均有抑制作用，有望成为治疗卵巢癌的潜在候选药物。(C)2017年爱思唯尔·马森公司。版权所有。
Glycogen synthase kinase 3 beta (GSK 3 beta) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3 beta inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3 beta. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non ATP competitive small molecule inhibitor of GSK 3 beta with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC. (C) 2017 Elsevier Masson SAS. All rights reserved.