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.
journal_name
Medchemcommjournal_title
MedChemCommauthors
Byun HS,Pyne S,Macritchie N,Pyne NJ,Bittman Rdoi
10.1039/C3MD00201Bsubject
Has Abstractpub_date
2013-01-01 00:00:00issue
10eissn
2040-2503issn
2040-2511journal_volume
4pub_type
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