Byun, H.-S., Pyne, S., MacRitchie, N., Pyne, N. J. and Bittman, R. (2013) Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells. MedChemComm, 4(10), pp. 1394-1399. (doi: 10.1039/C3MD00201B) (PMID:24396570) (PMCID:PMC3880124)
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Abstract
Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selective for SK2 whereas the 1-deoxysphinganines 55-21 and 77-7 are selective for SK1. (2S,3R)-1-Deoxysphinganine (55-21) induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitors PF-543 and VPC96091 failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as 55-21 are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by a British Heart Foundation grant (29476) to NJP/SP and by NIH Grant HL-083187 to RB. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | MacRitchie, Dr Neil |
| Authors: | Byun, H.-S., Pyne, S., MacRitchie, N., Pyne, N. J., and Bittman, R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | MedChemComm |
| Publisher: | Royal Society of Chemistry |
| ISSN: | 2040-2503 |
| ISSN (Online): | 2040-2511 |
| Published Online: | 06 August 2013 |
| Copyright Holders: | Copyright © 2013 The Royal Society of Chemistry |
| First Published: | First published in MedChemComm 4(10): 1394-1399 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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