(Meriolins (3) - pyrimidin-4-yl 7-azaindoles):合成、激酶抑制活性,细胞的影响,和CDK2 /细胞周期蛋白的结构/ meriolin复杂。

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Echalier, Bettayeb K, Ferandin Y, Lozach O,克莱门特M,瓦,狮虎F, Marquet B,莫里斯JC,恩迪科特杰,约瑟夫·B,梅耶尔L

(Meriolins (3) - pyrimidin-4-yl 7-azaindoles):合成、激酶抑制活性,细胞的影响,和CDK2 /细胞周期蛋白的结构/ meriolin复杂。

J医学杂志。2008年2月28日,51 (4):737 - 51。doi: 10.1021 / jm700940h。Epub 2008年1月31日。

PubMed ID

18232649 (在PubMed

]

文摘

我们报告的合成和生物特征3 - (pyrimidin-4-yl) 7-azaindoles (meriolins),天然产物之间的化学混合meridianins variolins,来自海洋生物。Meriolins显示有效抑制活动对细胞周期蛋白依赖性激酶(CDKs),以及在较小程度上,其他激酶(GSK-3 DYRK1A)。1 e (meriolin 5)的晶体结构和variolin B (Bettayeb k;Tirado o . m .;Marionneau-Lambert,美国;Ferandin y;Lozach o .;莫里斯,j .;Mateo-Lozano,美国;德鲁克,p; Schachtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
4 - (4-methoxy-1H-pyrrolo [2, 3 b] pyridin-3-yl) pyrimidin-2-amine	细胞周期蛋白依赖性激酶2	集成电路50 (nM)	11	N /一个	N /一个	细节
4 - (4-propoxy-1H-pyrrolo [2, 3 b] pyridin-3-yl) pyrimidin-2-amine	细胞周期蛋白依赖性激酶2	集成电路50 (nM)	3	N /一个	N /一个	细节