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 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

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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.

    Author(s):Byun, Hoe-Sup, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584, Macritchie, Neil, Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578 and Bittman, Robert
    Item type:Article
    ID code:49438
    Keywords:pulmonary arterial hypertension, cancer, novel sphingosine kinase 1, smooth muscle cell, Pharmacy and materia medica, Biochemistry, Pharmaceutical Science
    Subjects: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:10 Jan 2020 04:06
    URI:https://strathprints.strath.ac.uk/id/eprint/49438
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