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

Patwardhan, Neeraj N.; Morris, Emily A.; Kharel, Yugesh; Raje, Mithun; Gao, Ming; Tomsig, Jose L.; Santos, Webster L.

doi:10.1021/jm501760d

Cited by 68 publications

(103 citation statements)

References 52 publications

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“…6A and a previous report (Patwardhan et al, 2015). We dosed rats with SLC5111312, a dual SphK1/SphK2 inhibitor in this species, and observed that blood S1P was lowered to about 40% of the initial level (Fig.…”

Section: Sphk2 and Blood S1psupporting

confidence: 71%

“…Further, we have reported previously that i.v. administration of a SphK1 inhibitor rapidly depletes endogenous blood S1P in mice , and we have extended this observation to rats using a later generation SphK1 inhibitor (Patwardhan et al, 2015). Thus, the available data consistently indicate that blood S1P is replaced rapidly, at least in the species studied.…”

Section: Discussionmentioning

confidence: 54%

“…In contrast, at the rat enzymes, SLC5111312 is a nonselective inhibitor. We and others have observed a similar differential in potency between mouse and human SphK1 over a variety of chemical scaffolds (Schnute et al, 2012;Rex et al, 2013;Zhang et al, 2014;Patwardhan et al, 2015). Importantly, SLC5111312 provides a tool that is simultaneously a SphK2 selective (mouse) and dual SphK (rat and human) inhibitor.…”

Section: Sphk2 and Blood S1pmentioning

confidence: 55%

“…Mice with no functional SphK alleles die in utero, with no detectable S1P (Mizugishi et al, 2005). We have previously documented that the results of these genetic manipulations can be recapitulated with small-molecule inhibitors of SphKs in that administration of an SphK1 inhibitor to wild-type mice or rats decreases blood S1P Patwardhan et al, 2015), whereas administration of an SphK2 inhibitor to mice raises blood S1P levels (Kharel et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Kharel

Morris²,

Congdon³

et al. 2015

J Pharmacol Exp Ther

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Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitortreated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels.

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Section: Sphk2 and Blood S1psupporting

confidence: 71%

Section: Discussionmentioning

confidence: 54%

Section: Sphk2 and Blood S1pmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Kharel

Morris²,

Congdon³

et al. 2015

J Pharmacol Exp Ther

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“…In this new series, the amide moiety was replaced with three distinct oxadiazoles; the reasoning for this is 3-fold: (1) our previous inhibitors have displayed poor half-lives in vivo and oxadiazoles are well-documented amide surrogates, 23−27 (2) oxadiazoles have been effective structural subunits in our previous work with SphK2 substrates, 28 and (3) oxadiazole linkers improved the efficacy of guanidine-based SphK1 inhibitors. 17 As a starting point, 11c, an analogue of 2 and 3, was synthesized as follows (Scheme 1). First, 1-dodecene was reduced to the alkyl borane with 9-BBN and coupled to 4-bromobenzonitrile using Suzuki conditions to p-alkylbenzonitrile 7c.…”

mentioning

confidence: 99%

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles

Houck

Dawson

Kennedy

et al. 2016

ACS Med. Chem. Lett.

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Sphingosine 1-phosphate (S1P) is a potent growth-signaling lipid that has been implicated in cancer progression, inflammation, sickle cell disease, and fibrosis. Two sphingosine kinases (SphK1 and 2) are the source of S1P; thus, inhibitors of the SphKs have potential as targeted cancer therapies and will help to clarify the roles of S1P and the SphKs in other hyperproliferative diseases. Recently, we reported a series of amidinebased inhibitors with high selectivity for SphK1 and potency in the nanomolar range. However, these inhibitors display a short half-life. With the goal of increasing metabolic stability and maintaining efficacy, we designed an analogous series of molecules containing oxadiazole moieties. Generation of a library of molecules resulted in the identification of the most selective inhibitor of SphK1 reported to date (705-fold selectivity over SphK2), and we found that potency and selectivity vary significantly depending on the particular oxadiazole isomer employed. The best inhibitors were subjected to in silico molecular dynamics docking analysis, which revealed key insights into the binding of amidine-based inhibitors by SphK1. Herein, the design, synthesis, biological evaluation, and docking analysis of these molecules are described. KEYWORDS: Sphingosine 1-phosphate, sphingosine kinase, cancer, inhibitor, oxadiazoles S phingosine 1-phosphate (S1P) is a potent signaling lipid that acts on five membrane-bound receptors (S1P1−5) 1 and various intracellular targets. 2 S1P has been shown to regulate a host of processes that affect the growth and fate of cells, 3 and aberrant S1P signaling has been linked to numerous diseases including cancer, 2,4 asthma, 5 fibrosis, 6 and sickle cell disease. 7 Cellular synthesis of S1P is exclusively dependent on the action of two sphingosine kinases (SphK1 and 2) that directly phosphorylate sphingosine (Sph). 3 As the sole sources of cellular S1P, the SphKs influence cell survival 8,9 and have been identified as targets of interest in pharmacology and the pharmaceutical industry. 4,10 Therefore, SphK inhibitors, by affecting S1P levels, have therapeutic potential and are necessary to clarify the many roles of S1P and each SphK in physiology and disease. 10−12 S1P signaling is complex, and the roles of SphK1 and 2 in various pathways differ significantly. These differences are due, in large part, to subcellular compartmentalization; SphK2 possesses an N-terminal nuclear localization sequence not present in SphK1. 13 Indeed, SphK2 is located primarily in the nucleus and other organelles and may influence gene expression through S1P-dependent inhibition of histone deacetylase 1 and 2 (HDAC1 and 2). 14 Additionally, S1P produced by SphK2 in the endoplasmic reticulum and mitochondria has the effect of stimulating apoptosis. 15 In contrast, SphK1 is located primarily in the cytosol, and SphK1-derived S1P generally elicits prosurvival and proliferative effects through interactions with S1P1−5. Upon phosphorylation by the extracellular-regulated kinases, Sp...

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Synthesis and biological investigation of protein phosphatase 2A‐activating compounds with dimeric tail as non‐small cell lung cancer cell death agents

Kim

Lee

et al. 2022

Bulletin Korean Chem Soc

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FTY720 exerts an anticancer effect through the activation of protein phosphatase 2A (PP2A), which acts as a tumor suppressor, and inhibits SK1 activity. However, FTY720 taken into the body is phosphorylated by endogenous SK2. The structure of FTY720 is well‐studied as a basis for developing SK inhibitors and PP2A activators. We synthesized analogs of PF‐543 with a dimeric tail structure and reported the efficacy of SK1 inhibition. The compounds with this structure had improved anticancer activity and stability compared with PF‐543. To confirm whether the dimeric tail structure could be applied as a PP2A‐active material, we synthesized four types of compounds with a dimeric tail structure and confirmed the anticancer activity and PP2A activation in A549 non‐small cell lung cancer cells. Compounds 2 and 4 were more cytotoxic to A549 cells than RB005, and induced similar levels of cytotoxic and PP2A activation as FTY720.

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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

Cited by 68 publications

References 52 publications

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles

Synthesis and biological investigation of protein phosphatase 2A‐activating compounds with dimeric tail as non‐small cell lung cancer cell death agents

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