Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2).
Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2).
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DOI：
10.1016/j.bmc.2015.11.045
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发表时间：
2016-02-15
影响因子：
3.5
通讯作者：
Reddy EP
中科院分区：
文献类型：
--
作者：
Reddy MV;Akula B;Jatiani S;Vasquez-Del Carpio R;Billa VK;Mallireddigari MR;Cosenza SC;Venkata Subbaiah DR;Bharathi EV;Pallela VR;Ramkumar P;Jain R;Aggarwal AK;Reddy EP
已显示蛋白激酶的几个家族在细胞周期进展的调节中起关键作用，特别是通过有丝分裂的进展。这些激酶家族包括Aurora激酶、Mps 1基因产物和蛋白激酶（PLK）的波罗样家族。PLK家族由五个成员组成，其中PLK 1在人类癌症中的作用已得到充分证实。PLK 2（SNK）与PLK 1高度同源，已被证明在中心粒复制中起关键作用，并且还被认为通过在缺氧条件下物理稳定肿瘤细胞中的TSC 1/2复合物而在存活途径中起调节作用。作为我们研究计划的一部分，我们已经开发了一个新的ATP模拟化学型库，这些化学型对一组癌细胞系具有细胞毒性。我们发现，这些化学型之一，6-芳基磺酰基吡啶并嘧啶酮，诱导人肿瘤细胞系的纳摩尔浓度的凋亡。这些化合物中最有效的7ao被发现是PLK 2的高度特异性抑制剂，当针对一组288种野生型、55种突变体和12种脂质激酶进行分析时。本文介绍了先导化合物7ao的合成、构效关系、体外激酶特异性和生物活性。
Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.
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影响因子：
5.3
作者：
SIMMONS, DL;NEEL, BG;ERIKSON, RL
通讯作者：
ERIKSON, RL
（E）-N-芳基-2-芳基甲磺酰胺类似物的设计，合成和生物学评估是有效和口服可生物可用的微管靶向抗癌剂。
影响因子：
7.3
作者：
Reddy MV;Mallireddigari MR;Pallela VR;Cosenza SC;Billa VK;Akula B;Subbaiah DR;Bharathi EV;Padgaonkar A;Lv H;Gallo JM;Reddy EP
通讯作者：
Reddy EP
影响因子：
3.5
作者：
Reddy, MVR;Mallireddigari, MR;Reddy, EP
通讯作者：
Reddy, EP
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL
影响因子：
7.3
作者：
Friesner, Richard A.;Murphy, Robert B.;Mainz, Daniel T.
通讯作者：
Mainz, Daniel T.