A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay. PLoS One 2013;8(4):e53317
Date
05/10/2013Pubmed ID
23658603Pubmed Central ID
PMC3637257DOI
10.1371/journal.pone.0053317Scopus ID
2-s2.0-84876829069 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.
Author List
Lu J, Xin S, Meng H, Veldman M, Schoenfeld D, Che C, Yan R, Zhong H, Li S, Lin SAuthor
Matthew B. Veldman PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetanilidesAnimals
Antineoplastic Agents
Biological Assay
Cell Cycle Proteins
Dose-Response Relationship, Drug
Embryo, Nonmammalian
Glycine
High-Throughput Screening Assays
Humans
Male
Mice
Mice, Nude
Mitosis
Molecular Docking Simulation
Protein Kinase Inhibitors
Protein Structure, Tertiary
Proto-Oncogene Proteins
Quinolines
Small Molecule Libraries
Sulfones
Xenograft Model Antitumor Assays
Zebrafish
