A sphingosine 1-phosphate receptor 2 selective allosteric agonist

Hideo Satsu, Marie Therese Schaeffer, Miguel Guerrero, Adrian Saldana, Christina Eberhart, Peter Hodder, Charmagne Cayanan, Stephan Schürer, Barun Bhhatarai, Ed Roberts, Hugh Rosen, Steven J. Brown

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.

Original languageEnglish (US)
Pages (from-to)5373-5382
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2013

Keywords

  • Allosteric
  • GPCR
  • Molecular modeling
  • S1PR2
  • Signaling
  • Sphingosine 1-phosphate

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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  • Cite this

    Satsu, H., Schaeffer, M. T., Guerrero, M., Saldana, A., Eberhart, C., Hodder, P., Cayanan, C., Schürer, S., Bhhatarai, B., Roberts, E., Rosen, H., & Brown, S. J. (2013). A sphingosine 1-phosphate receptor 2 selective allosteric agonist. Bioorganic and Medicinal Chemistry, 21(17), 5373-5382. https://doi.org/10.1016/j.bmc.2013.06.012