Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues

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dc.contributor.authorPashikanti, Srinathen
dc.contributor.authorFoster, Daniel J.en
dc.contributor.authorKharel, Yugeshen
dc.contributor.authorBrown, Anne M.en
dc.contributor.authorBevan, David R.en
dc.contributor.authorLynch, Kevin R.en
dc.contributor.authorSantos, Webster L.en
dc.date.accessioned2023-03-10T20:08:37Zen
dc.date.available2023-03-10T20:08:37Zen
dc.date.issued2022-10-19en
dc.date.updated2023-03-10T19:51:20Zen
dc.description.abstractSphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five native G-protein coupled receptors (S1P1-5) to regulate cell growth, survival, and proliferation. S1P has been implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis. As key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmacologic intervention. In this report, we describe the design, synthesis, and biological evaluation of sphingosine kinase 2 (SphK2) inhibitors with a focus on systematically introducing rigid structures in the aliphatic lipid tail present in existing SphK2 inhibitors. Experimental as well as molecular modeling studies suggest that conformationally restricted "lipophilic tail" analogues bearing a bulky terminal moiety or an internal phenyl ring are useful to complement the "J"-shaped sphingosine binding pocket of SphK2. We identified 14c (SLP9101555) as a potent SphK2 inhibitor (Ki= 90 nM) with 200-fold selectivity over SphK1. Molecular docking studies indicated key interactions: the cyclohexyl ring binding in the cleft deep in the pocket, a trifluoromethyl group fitting in a small side cavity, and a hydrogen bond between the guanidino group and Asp308 (amino acid numbering refers to human SphK2 (isoform c) orthologue). In vitro studies using U937 human histiocytic lymphoma cells showed marked decreases in extracellular S1P levels in response to our SphK2 inhibitors. Administration of 14c (dose: 5 mg/kg) to mice resulted in a sustained increase of circulating S1P levels, suggesting target engagement.en
dc.description.versionPublished versionen
dc.format.extentPages 469-489en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1021/acsbiomedchemau.2c00017en
dc.identifier.eissn2694-2437en
dc.identifier.issn2694-2437en
dc.identifier.issue5en
dc.identifier.orcidBrown, Anne [0000-0001-6951-8228]en
dc.identifier.orcidSantos, Webster [0000-0002-4731-8548]en
dc.identifier.otherPMC9585524en
dc.identifier.pmid36281302en
dc.identifier.urihttp://hdl.handle.net/10919/114083en
dc.identifier.volume2en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36281302en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCanceren
dc.subjectRare Diseasesen
dc.titleSphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analoguesen
dc.title.serialACS Bio and Med Chem Auen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
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