Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach
Journal
EBioMedicine
Journal Volume
36
Pages
241-251
Date Issued
2018
Author(s)
Abstract
Background: Cdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial. Methods: Here, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library. Findings: Our data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents. Interpretation: The inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy. Fund: This work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan. ? 2018 The Author(s)
Subjects
Cancer therapy; Cdc7 inhibitor; Drug repositioning; Protein fragment complementation assay; Protein-protein interaction
SDGs
Other Subjects
adenosine triphosphate; antineoplastic agent; Cdc7 Kinase Inhibitor; cisplatin; clofoctol; Dbf4 dependent kinase; dequalinium; Drf1 dependent kinase; olive oil; plasmid DNA; protein kinase inhibitor; unclassified drug; antineoplastic agent; CDC7 protein, human; cell cycle protein; DBF4 protein, human; protein binding; protein kinase inhibitor; protein serine threonine kinase; antineoplastic activity; Article; autoradiography; bioluminescence; cancer therapy; carcinogenesis; cell death; cell viability; cell viability assay; controlled study; cytotoxicity; DNA damage; drug repositioning; drug screening; enzyme activity; flow cytometry; fluorescence microscopy; gene; growth inhibition; high throughput screening; human; human cell; immunoblotting; immunoprecipitation; irradiation; male; mouse; nonhuman; nuclear localization signal; peptide synthesis; polymerase chain reaction; priority journal; protein interaction; protein phosphorylation; protein protein interaction; randomized controlled trial; Renilla reniformis; Rluc gene; therapy effect; tumor growth; tumor volume; Western blotting; animal; antagonists and inhibitors; chemistry; disease model; dose response; drug development; drug effect; gene expression; metabolism; molecular model; molecularly targeted therapy; procedures; protein conformation; reporter gene; structure activity relation; tumor cell line; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Repositioning; Drug Screening Assays, Antitumor; Gene Expression; Genes, Reporter; High-Throughput Screening Assays; Humans; Male; Mice; Models, Molecular; Molecular Targeted Therapy; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Structure-Activity Relationship; Xenograft Model Antitumor Assays
Type
journal article