Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells.
J Med Chem
; 54(10): 3524-48, 2011 May 26.
Article
en En
| MEDLINE
| ID: mdl-21495716
ABSTRACT
Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Esfingosina
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Lisofosfolípidos
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Leucemia
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Regulación Leucémica de la Expresión Génica
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Fosfotransferasas (Aceptor de Grupo Alcohol)
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Amidinas
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2011
Tipo del documento:
Article