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Discovery and identification of PIM-1 kinase inhibitors through a hybrid screening approach
- Source :
- Molecular Diversity. 18:335-344
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
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.
- Subjects :
- Human leukemia
Protein Conformation
Drug Evaluation, Preclinical
Computational biology
Pharmacology
Catalysis
Human prostate
Inorganic Chemistry
Inhibitory Concentration 50
Proto-Oncogene Proteins c-pim-1
DU145
Cell Line, Tumor
hemic and lymphatic diseases
Drug Discovery
medicine
Humans
Physical and Theoretical Chemistry
Protein Kinase Inhibitors
Molecular Biology
Kinase
Chemistry
Pim-1 Kinase
Organic Chemistry
Cancer
General Medicine
medicine.disease
Molecular Docking Simulation
Cancer cell lines
Pharmacophore
Information Systems
Subjects
Details
- ISSN :
- 1573501X and 13811991
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Molecular Diversity
- Accession number :
- edsair.doi.dedup.....a5e238d7a266c1f432e367e8aec15dd1