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Checkpoint kinase 1 (Chk1), a serine/threonine kinase, plays a critical role in the regulation of the cell-cycle G2/M checkpoint.1-3) When DNA damage is detected in human cells, as a response, Chk1 is activated through ATM/ATR pathway. The activated Chk1 triggers the G2/M checkpoint, which arrests the cells in G2 to allow time for repairing their DNA. The inhibition of Chk1 kinase has been shown to result in abrogation of the G2/M checkpoint, which would permit premature mitotic entry in the presence of DNA damage, leading ultimately to cell death. [4][5][6] This suggests a potential therapeutic use of Chk1 inhibitors in cancer therapy; that is as sensitizing agents of DNA damaging drugs which are still a major component of cancer therapy.3,7-9) Indeed, several Chk1 inhibitors, including UCN-01 10) and SB-218078, 2,11) have been reported to be able to enhance the cytotoxicities of the standard DNA-damaging agents in vivo. In addition, selective Chk1 inhibitors are also helpful in the study of G2/M checkpoint signaling. 3,12) Therefore, development of Chk1 inhibitors has attracted much attention in recent years.Currently, many academic institutes and pharmaceutical companies have been involved in the development of Chk1 inhibitors. And a considerable number of compounds have been reported to have inhibitory potency against Chk1. Some compounds, such as PF-477736, AZD7762 and UCN-01, 9,12,13) have entered into clinical trials. Even so, discovering more potent Chk1 inhibitors with novel chemical structures are still needed and important in order to provide more lead candidates for the drug development.Quantitative structure-activity relationship (QSAR) methods, particularly three dimensional QSAR (3D-QSAR), have been demonstrated as an effective tool in discovering novel lead compounds.14,15) And pharmacophore modeling method is one of the best 3D-QSAR methods, which has been successfully applied to the drug discovery. [16][17][18][19][20] Thus, in this investigation, we shall first develop 3D pharmacophore models of Chk1 inhibitors based on the known Chk1 inhibitors. It is expected that the established pharmacophore models are able to correctly elucidate the QSAR of the Chk1 inhibitors. Then the best pharmacophore model obtained will be used to screen chemical libraries to identify new inhibitors against Chk1. ExperimentalPharmacophore Modeling All the pharmacophore modeling calculations were carried out by using CATALYST 4.11 software package (Accelrys, San Diego, U.S.A.).21) The common pharmacophore features necessary for potent Chk1 inhibitors were identified by HipHop program, and quantitative pharmacophore models were created by HypoRefine module within CATALYST.In pharmacophore modeling, the selection of training set compounds is critical to the quality of produced models. Each modeling algorithm has its own requirements that should be conformed to, particularly in the aspects of chemical structural diversity and bioactivity variation of the training set compounds. For the pharmacophore modeling algorithm ad...