Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
复制标题
DOI：
10.1021/jm401073p
复制
发表时间：
2014-02-13
影响因子：
7.3
通讯作者：
Reddy EP
中科院分区：
文献类型：
--
作者：
Reddy MV;Akula B;Cosenza SC;Athuluridivakar S;Mallireddigari MR;Pallela VR;Billa VK;Subbaiah DR;Bharathi EV;Vasquez-Del Carpio R;Padgaonkar A;Baker SJ;Reddy EP
伊马替尼是一种BCR-ABL抑制剂，用于治疗慢性粒细胞白血病，其成功为开发其他激酶抑制剂作为治疗药物创造了巨大的动力。然而，癌症的复杂性导致最近对开发具有低毒性特征的多激酶抑制剂的多药理学方法的兴趣。考虑到这一目标，我们分析了150多种新型氰基吡啶并嘧啶化合物，并确定了可用于设计强效激酶抑制剂的构效关系趋势。发现一种化合物8-环戊基-2-[4-（4-甲基-哌嗪-1-基）-苯基氨基]-7-氧代-7，8-二氢-吡啶并[2，3-d]嘧啶-6-腈（7 x）是最有活性的，在约30-100 nM的浓度下诱导肿瘤细胞凋亡。体外激酶谱分析显示，7 x是一种多激酶抑制剂，对CDK 4/细胞周期蛋白D1和ARK 5激酶具有强效抑制活性。在这里，我们报告的合成，构效关系，激酶抑制特性，在体外细胞毒性，并在体内肿瘤消退的研究，这种先导化合物。
The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure–activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30–100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure–activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
登录
查看更多内容
影响因子：
11.2
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
通讯作者：
Chen-Kiang, Selina
影响因子：
11.5
作者：
Flaherty, Keith T.;LoRusso, Patricia M.;Schwartz, Gary K.
通讯作者：
Schwartz, Gary K.
影响因子：
4.8
作者：
Fry, DW;Bedford, DC;Garrett, MD
通讯作者：
Garrett, MD
影响因子：
4.7
作者：
Grafstrom, RH;Pan, WJ;Hoess, RH
通讯作者：
Hoess, RH
影响因子：
11.4
作者：
Kitagawa, M;Higashi, H;Taya, Y
通讯作者：
Taya, Y