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).
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.
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurelio
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Carmen V
authors.initials: CV
authors.lastname: Scullino
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology , Frome Road, Adelaide South Australia 5000, Australia.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Pitman
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Sexton
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Oliver
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology , Frome Road, Adelaide South Australia 5000, Australia.
authors.forename: Lorena
authors.initials: L
authors.lastname: Davies
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Clayton, Victoria 3800, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rebello
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Clayton, Victoria 3800, Australia.
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology , Frome Road, Adelaide South Australia 5000, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Monash Institute of Pharmaceutical Science, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Flynn
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010088:Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C108138:dihydroceramide desaturase