Targeting ceramide metabolism with a potent and specific ceramide kinase inhibitor.
Ceramide kinase (CerK) produces the bioactive lipid ceramide-1-phosphate (C1P) and appears as a key enzyme for controlling ceramide levels. In this study, we discovered and characterized adamantane-1-carboxylic acid (2-benzoylamino-benzothiazol-6-yl)amide (NVP-231), a potent, specific, and reversible CerK inhibitor that competitively inhibits binding of ceramide to CerK. NVP-231 is active in the low nanomolar range on purified as well as cellular CerK and abrogates phosphorylation of ceramide, resulting in decreased endogenous C1P levels. When combined with another ceramide metabolizing inhibitor, such as tamoxifen, NVP-231 synergistically increased ceramide levels and reduced cell growth. Therefore, NVP-231 represents a novel and promising compound for controlling ceramide metabolism that may provide insight into CerK physiological function.
Graf
Christine
C
Novartis Institutes for BioMedical Research, Vienna, Austria.
Klumpp
Martin
M
Habig
Michael
M
Rovina
Philipp
P
Billich
Andreas
A
Baumruker
Thomas
T
Oberhauser
Berndt
B
Bornancin
Frédéric
F
D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000378:metabolism; D049449:Luminescence; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D018411:Spodoptera / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D005982:Glutathione Transferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase