Tubulin is a molecular target of the Wnt-activating chemical probe
| Autor: | Koji Yamamoto, Junji Matsui, Ken-ichi Kazetani, Yasunori Fukuda, Osamu Sano, Hidehisa Iwata |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Databases Factual Phenotypic screening Biochemistry Cell Line 03 medical and health sciences Genes Reporter Tubulin High-Throughput Screening Assays medicine Cluster Analysis Humans Benzodioxoles Molecular Biology Cellular Senescence Cell Proliferation Reverse pharmacology biology Tubulin Modulators Drug discovery Small molecule Wnt Proteins 030104 developmental biology Pyrimidines Mechanism of action Microscopy Fluorescence biology.protein medicine.symptom Metabolic Networks and Pathways Protein Binding Research Article |
| Zdroj: | BMC Biochemistry |
| ISSN: | 1471-2091 |
| Popis: | Background In drug discovery research, cell-based phenotypic screening is an essential method for obtaining potential drug candidates. Revealing the mechanism of action is a key step on the path to drug discovery. However, elucidating the target molecules of hit compounds from phenotypic screening campaigns remains a difficult and troublesome process. Simple and efficient methods for identifying the target molecules are essential. Results 2-Amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) was identified as a senescence inducer from a phenotypic screening campaign. The compound is widely used as a Wnt agonist, although its target molecules remain to be clarified. To identify its target proteins, we compared a series of cellular assay results for the compound with our pathway profiling database. The database comprises the activities of compounds from simple assays of cellular reporter genes and cellular proliferations. In this database, compounds were classified on the basis of statistical analysis of their activities, which corresponded to a mechanism of action by the representative compounds. In addition, the mechanisms of action of the compounds of interest could be predicted using the database. Based on our database analysis, the compound was anticipated to be a tubulin disruptor, which was subsequently confirmed by its inhibitory activity of tubulin polymerization. Conclusion These results demonstrate that tubulin is identified for the first time as a target molecule of the Wnt-activating small molecule and that this might have misled the conclusions of some previous studies. Moreover, the present study also emphasizes that our pathway profiling database is a simple and potent tool for revealing the mechanisms of action of hit compounds obtained from phenotypic screenings and off targets of chemical probes. Electronic supplementary material The online version of this article (doi:10.1186/s12858-016-0066-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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