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.
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 i = 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.
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