Structure-based rational design of staurosporine-based fluorescent probe with broad-ranging kinase affinity for kinase panel application
| Autor: | Masato Yoshikawa, Tomoya Sameshima, Yoshihiko Hirozane, Masashi Toyofuku, Yukiya Tanaka, Takatoshi Yogo, Ikuo Miyahisa |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Biosensing Techniques Biochemistry Binding Competitive Sensitivity and Specificity Acylation Methylamines Structure-Activity Relationship Drug Discovery medicine Fluorescence Resonance Energy Transfer Staurosporine Moiety Humans Protein kinase A Molecular Biology Protein Kinase Inhibitors Fluorescent Dyes Binding Sites Molecular Structure Chemistry Kinase Organic Chemistry Rational design Hydrogen Bonding Molecular Medicine Kinase binding Linker Protein Kinases medicine.drug Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(21) |
| ISSN: | 1464-3405 |
| Popis: | Selectivity profiling of compounds is important for kinase drug discovery. To this end, we aimed to develop a broad-range protein kinase assay by synthesizing a novel staurosporine-derived fluorescent probe based on staurosporine and kinase-binding related structural information. Upon structural analysis of staurosporine with kinases, a 4'-methylamine moiety of staurosporine was found to be located on the solvent side of the kinases, to which several linker units can be conjugated by either alkylation or acylation. However, such conjugation was suggested to reduce the binding affinities of the modified compound for several kinases, owing to the elimination of hydrogen bond donor moiety of NH-group from 4'-methylamine and/or steric hindrance by acyl moiety. Based on this structural information, we designed and synthesized a novel staurosporine-based probe without methyl group in order to retain the hydrogen bond donor, similar to unmodified staurosporine. The broad range of the kinase binding assay demonstrated that our novel fluorescent probe is an excellent tool for developing broad-ranging kinase binding assay. |
| Databáze: | OpenAIRE |
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