2. Academic Validation
  3. Structure guided design of a series of sphingosine kinase (SphK) inhibitors

Structure guided design of a series of sphingosine kinase (SphK) inhibitors

  • Bioorg Med Chem Lett. 2013 Aug 15;23(16):4608-16. doi: 10.1016/j.bmcl.2013.06.030.
Darin J Gustin 1,  Yihong Li,  Matthew L Brown,  Xiaoshan Min,  Mike J Schmitt,  Malgorzata Wanska,  Xiaodong Wang,  Richard Connors,  Sheere Johnstone,  Mario Cardozo,  Alan C Cheng,  Shawn Jeffries,  Brendon Franks,  Shyun Li,  Shanling Shen,  Mariwil Wong,  Holger Wesche,  Guifen Xu,  Timothy J Carlson,  Matthew Plant,  Kurt Morgenstern,  Karen Rex,  Joanna Schmitt,  Angela Coxon,  Nigel Walker,  Frank Kayser,  Zhulun Wang
Affiliations

Affiliation

  • 1 Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
PMID: 23845219 DOI: 10.1016/j.bmcl.2013.06.030
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.

Keywords

Drug design; Murine SphK; Sphingosine kinase 1 inhibitor; Sphingosine kinase 2 inhibitor; Structure based.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147282
    99.00%, SPHK1 Inhibitor