From sphingosine kinase to dihydroceramide desaturase: A structure-activity relationship (SAR) study of the enzyme inhibitory and anticancer activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)
| Autor: | Lorena T. Davies, Richard J. Rebello, Bernard L. Flynn, Darren J. Creek, Victoria L. Oliver, Anna E. Sexton, Luc Furic, Luigi Aurelio, Melissa R. Pitman, Stuart M. Pitson, Carmen V. Scullino |
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| Přispěvatelé: | Aurelio, Luigi, Scullino, Carmen V, Pitman, Melissa R, Sexton, Anna, Oliver, Victoria, Davies, Lorena, Rebello, Richard J, Furic, Luc, Creek, Darren J, Pitson, Stuart M, Flynn, Bernard L |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
enzyme inhibitory Cell Survival Sphingosine kinase Antineoplastic Agents Pharmacology Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Drug Discovery Humans Structure–activity relationship Inducer Sphingosine-1-phosphate sphingolipid metabolites Enzyme Inhibitors Cell Proliferation Dose-Response Relationship Drug Molecular Structure Cell growth Dihydroceramide desaturase In vitro Phosphotransferases (Alcohol Group Acceptor) Thiazoles 030104 developmental biology anticancer activity chemistry Biochemistry 030220 oncology & carcinogenesis dihydroceramide desaturase Molecular Medicine Drug Screening Assays Antitumor Oxidoreductases |
| Popis: | The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure-activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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