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
Byun, Hoe-Sup and Pyne, Susan and Macritchie, Neil and Pyne, Nigel J and Bittman, Robert (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. ISSN 2040-2503 (https://doi.org/10.1039/C3MD00201B)
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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.
ORCID iDs
Byun, Hoe-Sup, Pyne, Susan ORCID: https://orcid.org/0000-0002-6608-9584, Macritchie, Neil, Pyne, Nigel J ORCID: https://orcid.org/0000-0002-5657-4578 and Bittman, Robert;-
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Item type: Article ID code: 49438 Dates: DateEvent1 October 2013Published6 August 2013Published OnlineSubjects: Medicine > Pharmacy and materia medica Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 01 Oct 2014 08:51 Last modified: 20 Oct 2024 13:03 URI: https://strathprints.strath.ac.uk/id/eprint/49438