Sphingosine Kinases: Biochemistry, Regulation, and Roles

Pitman, Melissa R.; Jarman, Kate E.; Leclercq, Tamara; Pham, Duyen; Pitson, Stuart M.

doi:10.1002/9781118531426.ch9

Cited by 1 publication

(2 citation statements)

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“…Therefore, we employed homology modeling to predict the structure of the ATP-binding pocket of SK1 using the solved structures of two bacterial lipid kinases, DgkB [29] and YegS [30] that, while possessing little overall sequence similarity to SK1, do show some sequence similarity with residues proposed to contribute to ATP binding in SK1 [1, 28, 31] (Supplementary Figure 1). In the model (Figure 1A), residues from all five regions highly conserved in the SKs (Motifs 1–5; Supplementary Figure 1) were involved in forming the ATP-binding pocket of SK1, with the 79 SGDGLMHE 86 motif forming the centre of the pocket.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, unlike some other recently developed SK inhibitors [26], comparable inhibition of murine SK1 and SK2 was also observed (Figure 1F). We also examined the inhibitory activity of MP-A08 against the related human lipid kinases, diacylglycerol kinase (DAGK) and ceramide kinase (CERK), which both show considerable polypeptide sequence similarity to the SKs in most of the conserved regions involved in forming the ATP-binding pocket [31] (Motifs 1–5). Notably, MP-A08 showed no inhibition of human DAGK, and only weakly inhibited CERK when employed at 192 μM (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

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A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties

et al. 2015

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The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes.

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