title: Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits.
abstract: Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magnitude improved potency. Compound 22a inhibited SphK1 with an IC50of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors.
authors.forename: Mark E
authors.identifier: 0000-0003-3075-4578
authors.initials: ME
authors.lastname: Schnute
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McReynolds
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Carroll
authors.affiliation: Medicine Design, Pfizer , Groton, Connecticut 06340, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Chrencik
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Highkin
authors.forename: Kaliapan
authors.initials: K
authors.lastname: Iyanar
authors.forename: Gina
authors.initials: G
authors.lastname: Jerome
authors.forename: John W
authors.initials: JW
authors.lastname: Rains
authors.forename: Matthew
authors.initials: M
authors.lastname: Saabye
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Scholten
authors.forename: Matthew
authors.initials: M
authors.lastname: Yates
authors.forename: Marek M
authors.initials: MM
authors.lastname: Nagiec
mesh_terms: D000586:Amination; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D001562:Benzimidazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D000099157:Sphingosine Kinase; C032519:pyrrolidine