期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 -, 页码 30-38出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.08.007
关键词
Casein kinase 1; Pharmacophore; Virtual screening; Lead optimization; Cancer; Central nervous system disorders
资金
- National Natural Science Foundation of China [81172987]
- SRFDP [20100181110025]
- 863 Hi-Tech Program [2012AA020301, 2012AA020308]
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.
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