title: Structure guided design of a series of sphingosine kinase (SphK) inhibitors.
abstract: Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
authors.affiliation: Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Gustin
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Brown
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Min
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Schmitt
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wanska
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Connors
authors.forename: Sheere
authors.initials: S
authors.lastname: Johnstone
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Shawn
authors.initials: S
authors.lastname: Jeffries
authors.forename: Brendon
authors.initials: B
authors.lastname: Franks
authors.forename: Shyun
authors.initials: S
authors.lastname: Li
authors.forename: Shanling
authors.initials: S
authors.lastname: Shen
authors.forename: Mariwil
authors.initials: M
authors.lastname: Wong
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carlson
authors.forename: Matthew
authors.initials: M
authors.lastname: Plant
authors.forename: Kurt
authors.initials: K
authors.lastname: Morgenstern
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Joanna
authors.initials: J
authors.lastname: Schmitt
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020033:Protein Isoforms / Q000737:chemistry; D051381:Rats; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D020033:Protein Isoforms; D054852:Small Molecule Libraries; D000099157:Sphingosine Kinase
keywords: Drug design; Murine SphK; Sphingosine kinase 1 inhibitor; Sphingosine kinase 2 inhibitor; Structure based