期刊
MOLECULES
卷 27, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/molecules27103346
关键词
sphingosine kinase; PF-543; anticancer; inhibitor; protein phosphatase 2A
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [2020R1A2C1012156, 2020R1F1A1068316]
- National Research Foundation of Korea [2020R1A2C1012156] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
This study found that the tail structure of PF-543 influences its metabolic stability. Compounds with aliphatic tails have high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1.
Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes-SK1 and SK2-is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS.
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