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KMID : 0370220180620050293
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Yakhak Hoeji
2018 Volume.62 No. 5 p.293 ~ p.296
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Antitumor activity of PF-543 and PF-543 derivative (22c) as sphingosine kinase 1 inhibitors
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Baek Dong-Jae
Park Eun-Young
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Abstract
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PF-543 selectively inhibits sphingosine kinase (SK)1 most potently among the known SK inhibitors. Although SK1 inhibitors have been reported to have anticancer effect, PF-543 has lower anticancer activity in some cancer cells compared with selective inhibition of SK1. Recent PF-543 derivatives were synthesized in Pfizer and observed inhibitory effects on SK1, suggesting that (S)-1-(4-((3-methyl-5-((phenylsulfonyl)methyl)phenoxy)methyl)benzyl)pyrrolidin-3-ol (22c) is more effective than PF-543. We investigated whether 22c improved the anticancer activity compared to PF-543 in proportion to the SK-1 inhibitory effect. The cytotoxic effect of PF-543, 22c and 5-fluorouracil was compared in HT29, HCT116 and AGS cells. PF-543 showed slightly higher cytotoxic effect than 22c in all cells. These results suggest that the SK inhibitory activity and the anticancer effect of the SK inhibitor are not necessarily proportional to each other. Therefore, development of SK inhibitor as an anticancer agent requires comparison of anticancer activity.
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KEYWORD
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sphingosine kinase, inhibitor, PF-543, cancer, derivative
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