Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization

被引:40
作者
Yang, Ling-Ling [1 ,2 ]
Li, Guo-Bo [1 ]
Yan, Heng-Xiu [1 ]
Sun, Qi-Zheng [1 ]
Ma, Shuang [1 ]
Ji, Pan [1 ]
Wang, Ze-Rong [1 ]
Feng, Shan [1 ]
Zou, Jun [1 ]
Yang, Sheng-Yong [1 ]
机构
[1] Sichuan Univ, State Key Lab Biotherapy, W China Hosp, W China Med Sch, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, Coll Chem Engn, Chengdu 610041, Sichuan, Peoples R China
基金
中国国家自然科学基金;
关键词
Casein kinase 1; Pharmacophore; Virtual screening; Lead optimization; Cancer; Central nervous system disorders; FLEXIBLE DOCKING; CASEIN KINASE-1; DRUG DISCOVERY; IDENTIFICATION; FAMILY; PHOSPHORYLATION; CASEIN-KINASE-1; LIMITATIONS; TARGETS; LIGAND;
D O I
10.1016/j.ejmech.2012.08.007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo [3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM. (c) 2012 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:30 / 38
页数:9
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