title: Discovery and identification of PIM-1 kinase inhibitors through a hybrid screening approach.
abstract: PIM-1 kinase is an important therapeutic target in the treatment of cancer. Discovery and identification of PIM-1 Inhibitors with novel scaffolds are an effective way for developing potent therapeutic agents for the treatment of cancers. Here we proposed a hybrid screening approach which combines an optimal structure-based drug design strategy and a simple pharmacophore model to discover PIM-1 kinase inhibitors. With the proposed hybrid screening approach, the SPECS database containing 204,580 molecules was screened. In total, 89 hits were obtained. Forty three of them were purchased and tested in bioassays. Finally, 5 lead compounds with novel scaffolds were identified to exhibit promising antitumor activities against human leukemia cell line MV4-11, K-562 and human prostate cancer cell line PC-3 and DU145. Their IC(50) values range from 4.40 to 37.96 μM. Three hits with 3 different scaffolds were selected from these five hits for binding mode analysis. It was demonstrated that the subtle differences in the interactions of the representatives with PIM-1 kinase contribute to the different inhibitory activities. It was also demonstrated that the suggested hybrid screening approach is an effective method to discover PIM-1 inhibitors possessing different scaffolds. These leads have a strong likelihood to act as further starting points for us in the optimization and development of potent PIM-1 inhibitors.
authors: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, # 1 Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu , 610041, China.
authors: Mingfeng
authors: M
authors: Shao
authors: Yiming
authors: Y
authors: Yuan
authors: Kun
authors: K
authors: Yu
authors: Kai
authors: K
authors: Lei
authors: Guonian
authors: G
authors: Zhu
authors: Lijuan
authors: L
authors: Chen
authors: Mingli
authors: M
authors: Xiang
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1