Author: Maceyka, Michael ; Jampilek, Josef ; Senkal, Can E ; Gräler, Markus H ; Enriz, Ricardo D ; Spiegel, Sarah ; Lima, Santiago ; Newton, Jason ; Weigel, Cynthia ; Palladino, Elisa N D ; Marvanova, Pavlina ; Milstien, Sheldon

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

01 Jan 2019·European Journal of PharmacologyQ3 · MEDICINE

Requirement for sphingosine kinase 1 in mediating phase 1 of the hypotensive response to anandamide in the anaesthetised mouse

Q3 · MEDICINE

Article

Author: Fertig, Bracy ; Ewart, Marie-Ann ; Alganga, Husam ; Ballantyne, Margaret D ; Pyne, Susan ; Nather, Katrin ; Zaborska, Karolina E ; Greig, Fiona H ; Kennedy, Simon ; Pyne, Nigel J ; Kazi, Zeshan H

In the isolated rat carotid artery, the endocannabinoid anandamide induces endothelium-dependent relaxation via activation of the enzyme sphingosine kinase (SK). This generates sphingosine-1-phosphate (S1P) which can be released from the cell and activates S1P receptors on the endothelium. In anaesthetised mice, anandamide has a well-characterised triphasic effect on blood pressure but the contribution of SK and S1P receptors in mediating changes in blood pressure has never been studied. Therefore, we assessed this in the current study. The peak hypotensive response to 1 and 10 mg/kg anandamide was measured in control C57BL/6 mice and in mice pretreated with selective inhibitors of SK1 (BML-258, also known as SK1-I) or SK2 ((R)-FTY720 methylether (ROMe), a dual SK1/2 inhibitor (SKi) or an S1P₁ receptor antagonist (W146). Vasodilator responses to S1P were also studied in isolated mouse aortic rings. The hypotensive response to anandamide was significantly attenuated by BML-258 but not by ROMe. Antagonising S1P₁ receptors with W146 completely blocked the fall in systolic but not diastolic blood pressure in response to anandamide. S1P induced vasodilation in denuded aortic rings was blocked by W146 but caused no vasodilation in endothelium-intact rings. This study provides evidence that the SK1/S1P regulatory-axis is necessary for the rapid hypotension induced by anandamide. Generation of S1P in response to anandamide likely activates S1P₁ to reduce total peripheral resistance and lower mean arterial pressure. These findings have important implications in our understanding of the hypotensive and cardiovascular actions of cannabinoids.

01 Nov 2018·Breast Cancer Research and TreatmentQ2 · MEDICINE

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Q2 · MEDICINE

Article

Author: Pchejetski, Dmitri ; Wang, Qi ; Low, Caroline M R ; Alshaker, Heba ; Monteil, Danielle ; Srivats, Shyam

PURPOSESphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile.METHODSField template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models.RESULTSField template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity.CONCLUSIONThrough field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX.

100 Deals associated with SK1-I

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	IND Application	US	Enzo Biochem, Inc.	03 Dec 2018
Acute Myeloid Leukemia	IND Application	US	Enzo Biochem, Inc.	03 Dec 2018
Breast Cancer	IND Application	US	Enzo Biochem, Inc.	03 Dec 2018
Glioblastoma	IND Application	US	Enzo Biochem, Inc.	03 Dec 2018
Liver Cancer	Preclinical	US	Enzo Biochem, Inc.	-
COVID-19	Discovery	US	Enzo Biochem, Inc.	22 Apr 2020
Respiratory Insufficiency	Discovery	US	Enzo Biochem, Inc.	22 Apr 2020
Colitis, Ulcerative	Discovery	US	Enzo Biochem, Inc.	19 Feb 2020
Hepatitis, Autoimmune	Discovery	US	Enzo Biochem, Inc.	19 Feb 2020
Systemic Lupus Erythematosus	Discovery	US	Enzo Biochem, Inc.	19 Feb 2020

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