title: Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules.
abstract: There is considerable evidence that sphingosine kinases play a key role in cancer progression, which might involve positive selection of cancer cells that have been provided with a survival and growth advantage as a consequence of overexpression of the enzyme. Therefore, inhibitors of sphingosine kinase represent a novel class of compounds that have potential as anticancer agents. Poor inhibitor potency is a major issue that has precluded successful translation of these compounds into the clinic. However, recent discoveries have shown that sphingosine kinase 1 is an allosteric enzyme and that some inhibitors offer improved effectiveness by inducing proteasomal degradation of the enzyme or having nanomolar potency. Herein, we provide a perspective about these recent developments and highlight the importance of translating basic pharmacologic and biochemical findings on sphingosine kinase into new drug discovery programs for treatment of cancer.
authors.affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK. susan.pyne@strath.ac.uk
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D014753:Vinyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D009363:Neoplasm Proteins; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D013110:Sphingosine; D014753:Vinyl Compounds; D000099157:Sphingosine Kinase; C542743:((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid; C060506:sphingosine 1-phosphate