Discovery of novel sphingosine kinase 1 inhibitors

Xiang, Yibin; Asmussen, Gary; Booker, Michael L.; Hirth, Bradford; Kane, John L.; Liao, Junkai; Noson, Kevin; Yee, Christopher

doi:10.1016/j.bmcl.2009.09.022

Cited by 44 publications

(30 citation statements)

References 14 publications

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“…Another new generation selective SK1 inhibitor is Genzyme 51, with an IC 50 around 60 nM, an acceptable pharmacokinetic profile and SK2 inhibition at concentrations close to 10 µM. (Xiang et al, 2010(Xiang et al, , 2009). …”

Section: Selective Sk1 Inhibitorsmentioning

confidence: 99%

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

Sanllehí

Abad

Casas

et al. 2016

Chemistry and Physics of Lipids

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Section: Selective Sk1 Inhibitorsmentioning

confidence: 99%

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

Sanllehí

Abad

Casas

et al. 2016

Chemistry and Physics of Lipids

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“…Guanidine analogues of sphingosine have been developed as SK1 inhibitors, with LCL351 exhibiting nanomolar affinity for SK1 (IC 50 of 40 nM) and N 7-fold selectivity for SK2 [145]. Genzyme have also developed two SK1-selective compounds based on the sphingosine scaffold, termed 51 and 54, with in vitro IC 50 values of 58 and 10 nM, respectively, which display modest oral bioavailability in rats with reasonable blood half-lives [146,147].…”

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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“…9ab (Figure 2.5) was their most potent inhibitor displaying selectivity for SphK1 over SphK2 with K I values of 1.4 μM and 31 μM, respectively, which is much more potent and selective than DMS. 44,46 During the development of their series, they determined that the amide bond was essential for activity at the kinases. 44 Once the structure is fully optimized, the potency may increase making it an excellent tool to investigate the role of SphK1 in the 'Sphingolipid Rheotat'.…”

Section: Sphingosine-based Inhibitorsmentioning

confidence: 99%

“…44,46 During the development of their series, they determined that the amide bond was essential for activity at the kinases. 44 Once the structure is fully optimized, the potency may increase making it an excellent tool to investigate the role of SphK1 in the 'Sphingolipid Rheotat'. To combine the structures of sphingosine and FTY720, SG-12 was synthesized and displayed no activity against SphK1.…”

Section: Sphingosine-based Inhibitorsmentioning

confidence: 99%

“…Neither inhibitor is a good tool to elucidate the roles of the SphKs, but despite this, DMS is the industry standard since it has been vastly researched. 19,44 In an effort to synthesize an inhibitor that resembles the natural substrate, sphingosine, Wong et al developed inhibitors that would be more selective for the SphKs in comparison to DHS and DMS. This would allow researchers to properly probe the roles of these enzymes without having to worry about off-target effects.…”

Section: Sphingosine-based Inhibitorsmentioning

confidence: 99%

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Amidine-based Sphingosine Kinase Inhibitors: Optimization of Selectivity, Solubility, and Metabolism

Bolden

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Soon cancer will be the leading cause of death in the United States; unfortunately, the treatments available to patients have severe side effects.Chemotherapies target dividing cells with the goal to kill the rapidly dividing cancer cells before the patient. Researchers have been focusing on determining the cause of the disease and developing better modes of treatment. This has been difficult due to cancer developing resistance to drugs over time and the vast differences among the different types of the disease. One strategy is to develop targeted therapies that inhibit a particular pathway cancer cells rely on to survive.One such pathway is the "Sphingolipid Rheostat" and targeting either the production and/or signaling of sphingosine 1-phosphate (S1P). The research herein describes the design and synthesis of amidine-based inhibitors of the sphingosine kinases (SphKs) to limit the production of S1P since they are the sole producers of the molecule.Signaling by S1P leads to cell migration, proliferation, and survival. There are two isoforms of the SphKs, SphK1 and SphK2. Of the two, SphK1 has been studied much more since higher concentrations of this enzyme have been found in a variety of cancer cell lines. Our lab has been very successful in selectively targeting SphK1 using amidine-based inhibitors. These molecules lower S1P levels in vitro as well as in vivo. Only recently has SphK2 been more intensely investigated and found to play a more complex role in cell fate. S1P produced by this enzyme, depending on its cellular location, will either lead to cell migration ii and survival or apoptosis. These contradicting roles of the same endogenous molecule have left researchers needing further understanding of SphK2's roles in cell fate. The development of potent dual and sub-type selective inhibitors will be useful in elucidating the cellular roles of each of these kinases. Herein is described an attempt to selectively target SphK2 over SphK1 using amidinebased inhibitors. Structure-activity relationship (SAR) studies were performed on these molecules and it was found that these molecules bind to SphK2 at approximately equal strength. These studies lead us to believe that SphK2 is a promiscuous protein that will bind molecules with a variety of functionalization at similar strength.The Macdonald laboratory has developed some of the most potent SphK1-selective inhibitors in the chemical literature. In order to use these molecules in whole animal studies, they must be long-lived. Unfortunately, these amidine-based inhibitors have a short half-life due to their quick metabolism. The amide linkage of these molecules has been replaced with more metabolically stable 5-membered heterocycles to circumvent this issue. SAR studies were performed on these heterocyclic inhibitors to determine the optimal heterocycle to increase potency, selectivity, and half-life. These heterocyclic inhibitors were found to increase the half-life of the amidine-based SphK inhibitors and are equipotent to their amide counterparts. The...

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Discovery of novel sphingosine kinase 1 inhibitors

Cited by 44 publications

References 14 publications

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

Recent advances in the development of sphingosine kinase inhibitors

Amidine-based Sphingosine Kinase Inhibitors: Optimization of Selectivity, Solubility, and Metabolism

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