Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B
| Autor: | Go Hirai, Prakash T. Parvatkar, Yosei Nagaoka, Junko Ohkanda |
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| Rok vydání: | 2021 |
| Předmět: |
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Molecular CDC25A Clinical Biochemistry Phosphatase Pharmaceutical Science Biochemistry Protein–protein interaction Dephosphorylation chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain Drug Discovery Humans cdc25 Phosphatases Enzyme Inhibitors Molecular Biology Triazine biology Dose-Response Relationship Drug Molecular Structure Kinase Triazines Organic Chemistry Rational design Active site Combinatorial chemistry chemistry Drug Design biology.protein Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 48 |
| ISSN: | 1464-3405 |
| Popis: | Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration. |
| Databáze: | OpenAIRE |
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