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https://hdl.handle.net/2440/99358
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Type: | Journal article |
Title: | 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) |
Author: | Aurelio, L. Scullino, C.V. Pitman, M.R. Sexton, A. Oliver, V. Davies, L. Rebello, R.J. Furic, L. Creek, D.J. Pitson, S.M. Flynn, B.L. |
Citation: | Journal of Medicinal Chemistry, 2016; 59(3):965-984 |
Publisher: | American Chemical Society |
Issue Date: | 2016 |
ISSN: | 0022-2623 1520-4804 |
Statement of Responsibility: | Luigi Aurelio, Carmen V. Scullino, Melissa R. Pitman, Anna Sexton, Victoria Oliver, Lorena Davies, Richard J. Rebello, Luc Furic, Darren J. Creek, Stuart M. Pitson and Bernard L. Flynn |
Abstract: | 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. |
Keywords: | Cell Line, Tumor Humans Thiazoles Oxidoreductases Phosphotransferases (Alcohol Group Acceptor) Antineoplastic Agents Enzyme Inhibitors Drug Screening Assays, Antitumor Cell Proliferation Cell Survival Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug |
Rights: | Copyright © 2016 American Chemical Society |
DOI: | 10.1021/acs.jmedchem.5b01439 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1042589 http://purl.org/au-research/grants/nhmrc/1004695 http://purl.org/au-research/grants/nhmrc/1088855 |
Published version: | http://dx.doi.org/10.1021/acs.jmedchem.5b01439 |
Appears in Collections: | Aurora harvest 7 Molecular and Biomedical Science publications |
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