Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.
Autor: | Pashikanti S; Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24060, United States.; Department of Biomedical and Pharmaceutical Sciences, Idaho State University, Pocatello, Idaho 83209, United States., Foster DJ; Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24060, United States., Kharel Y; Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States., Brown AM; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24060, United States.; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24060, United States., Bevan DR; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24060, United States.; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24060, United States., Lynch KR; Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States., Santos WL; Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24060, United States.; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24060, United States. |
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Jazyk: | angličtina |
Zdroj: | ACS bio & med chem Au [ACS Bio Med Chem Au] 2022 Oct 19; Vol. 2 (5), pp. 469-489. Date of Electronic Publication: 2022 Jun 29. |
DOI: | 10.1021/acsbiomedchemau.2c00017 |
Abstrakt: | Sphingosine 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 ( K Competing Interests: The authors declare the following competing financial interest(s): W.L.S. and K.R.L. are among the co-founders of Flux Therapeutics Inc, which was created to commercialize S1P-related discoveries, including SphK inhibitors, discovered and characterized in their laboratories. (© 2022 The Authors. Published by American Chemical Society.) |
Databáze: | MEDLINE |
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