Recent advances in the development of sphingosine kinase inhibitors.
Sphingosine kinase (SK) 1 and 2 are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule with a wide array of cellular effects. SK1 and 2 have been shown to be up-regulated in tumours and their genetic ablation or inhibition has been shown to slow tumour growth as well as sensitise cancer cells to chemotherapeutics. The SKs have been extensively studied, with a plethora of inhibitors developed that target the sphingosine-binding pocket of the enzyme, some with nanomolar affinities. Recently, inhibitors targeting the ATP pocket of SK have also been described. Here we discuss the development of these new small molecule SK inhibitors, summarise the recent discovery of off-targets effects of many current SK inhibitors, and provide an overview of the usefulness of these inhibitors as in vitro tools and therapeutic agents.
Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia.
Melissa R
MR
Pitman
Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia; School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia.
Maurizio
M
Costabile
Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia. Electronic address: stuart.pitson@unisa.edu.au.
Stuart M
SM
Pitson
D000818:Animals; D055785:Gene Knockdown Techniques; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D000099157:Sphingosine Kinase
Ceramide; Sphingosine; Sphingosine kinase 1; Sphingosine kinase 2; Sphingosine-1-phosphate