Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors

Raje, Mithun; Knott, Kenneth; Kharel, Yugesh; Bissel, Philippe; Lynch, Kevin R.; Santos, Webster L.

doi:10.1016/j.bmc.2011.11.011

Cited by 35 publications

(31 citation statements)

References 49 publications

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“…38,41 Compound trans - 12b was shown to be ~8-fold selective toward SphK2 with a K i of 8 μM (Figure 1). The inhibition data validated our hypothesis that a positive charge is essential for electrostatic interaction, perhaps with the catalytic Asp residues on SphKs, which has been shown to be important for recognition of Sph by the enzyme.…”

Section: Resultsmentioning

confidence: 99%

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Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors

et al. 2015

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Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1–5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2, and hence, inhibitors of this phosphorylation step are pivotal in understanding the physiological functions of SphKs. To date, SphK1 and 2 inhibitors with the potency, selectivity, and in vivo stability necessary to determine the potential of these kinases as therapeutic targets are lacking. Herein, we report the design, synthesis, and structure–activity relationship studies of guanidine-based SphK inhibitors bearing an oxadiazole ring in the scaffold. Our studies demonstrate that SLP120701, a SphK2-selective inhibitor (Ki = 1 μM), decreases S1P levels in histiocytic lymphoma (U937) cells. Surprisingly, homologation with a single methylene unit between the oxadiazole and heterocyclic ring afforded a SphK1-selective inhibitor in SLP7111228 (Ki = 48 nM), which also decreased S1P levels in cultured U937 cells. In vivo application of both compounds, however, resulted in contrasting effect in circulating levels of S1P. Administration of SLP7111228 depressed blood S1P levels while SLP120701 increased levels of S1P. Taken together, these compounds provide an in vivo chemical toolkit to interrogate the effect of increasing or decreasing S1P levels and whether such a maneuver can have implications in disease states.

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Section: Resultsmentioning

confidence: 99%

“…34 Hence, attributing ABC294640 effects to SphK2 is difficult. Other inhibitors such as SG-12, 35 (R)-FTY720-OMe, 36 K145, 37 and trans - 12b 38 are reported as SphK2 inhibitors, albeit with moderate potency and selectivity. Hence, new scaffolds with the potency and selectivity are needed to investigate SphK1 and 2 functions in vivo.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors

et al. 2015

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“…Optimization of an initial hit compound produced a potent compound, named C2, which was found to be a novel SK1 inhibitor with an IC 50 of 63 nM, with N 500-fold selectivity over SK2 and selectivity over a panel of 62 lipid and protein kinases [148]. Studies have also investigated analogues of SKI-II [67,149], RB-005 [150], FTY720 [78,136,143,151,152] and SLR080811 [153]. Additionally, analogues of novel compounds extracted from natural products, like the SK2 inhibitor (2S,3S,4R)-Pachastrissamine [154,155] and the low-potency SK1 inhibitor belanocarpol, a dimer of resveratrol, have been reported [156].…”

Section: Other Sk Inhibitorsmentioning

confidence: 99%

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

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Sphingosine kinase (SK) 1 and 2 are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule with a wide array of cellular effects. SK1 and 2 have been shown to be up-regulated in tumours and their genetic ablation or inhibition has been shown to slow tumour growth as well as sensitise cancer cells to chemotherapeutics. The SKs have been extensively studied, with a plethora of inhibitors developed that target the sphingosine-binding pocket of the enzyme, some with nanomolar affinities. Recently, inhibitors targeting the ATP pocket of SK have also been described. Here we discuss the development of these new small molecule SK inhibitors, summarise the recent discovery of off-targets effects of many current SK inhibitors, and provide an overview of the usefulness of these inhibitors as in vitro tools and therapeutic agents.

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“…Our first generation inhibitor, VT-ME6 , contained a quaternary ammonium group as a warhead and established that a positively charged moiety is necessary for engaging key amino acid residues in the enzyme binding pocket. 13,14 This compound is moderately potent ( K i = 8 µM) and displays three-fold selectivity for SphK2 over SphK1. Subsequent improvement resulted in a scaffold that featured a 1,2,4-oxadiazole linker and guanidine as warhead: SLR080811 possesses a K i of 13.3 µM and 1.3 µM for SphK1 and SphK2 respectively.…”

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Structure–activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors

Congdon

Childress

Gumkowski

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies on the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1.

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Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors

Cited by 35 publications

References 49 publications

Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors

Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors

Recent advances in the development of sphingosine kinase inhibitors

Structure–activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors

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