Identification of Pim-1 Kinase Inhibitors by Pharmacophore Model, Molecular Docking-based Virtual Screening, and Biological Evaluation

Aim: This study aimed at screening and development of Pim-1 inhibitors as anticancer agent. Background: Pim-1, a member of the Ser/Thr kinase family, plays a crucial role in cell proliferation and is being regarded as a promising target for cancer therapeutics. Objective: The present work focused on screening more potent Pim-1 inhibitors by in-silico method and biological evaluation. Materials and Methods: To identify more potent Pim-1 inhibitors, a GALAHAD pharmacophore model was constructed based on nine known Pim-1 inhibitors and followed by in silico screening including pharmacophore and molecular docking-based virtual screening. The hit compounds were further assessed the Pim-1, 2, and 3 kinase activities and the anticancer inhibition property against human myeloma RPMI-8226 and U266 cells using cytotoxicity studies. Results: Based on Qfit value (from pharmacophore), docking score and clustering analysis, six compounds including C445_0268, C470_0769, 4456_0744, 0806_0325, G395_1510 and V023_3227 were hit. Binding mode analysis showed that hydrogen bond, hydrophobic and pi-pi stacking interactions dominated the bindings of these compounds to Pim-1. The further biological evaluation indicated that compounds C445_0268 and C470_0769 possessed excellent pan-Pim kinase activities and inhibited the growths of RPMI-8226 and U266 cell lines with IC50 values lower than 3.75 mu M. Conclusion: We reported a series of Pim-1 small molecule inhibitors that could serve as the lead compounds to develop new targeted anticancer therapeutics.