Sphingosine kinase 1 (SphK1) is the key enzyme catalyzing the formation of sphingosine-1-phosphate (S1P), which is an important signaling molecule regulating multiple biological process including inflammatory responses. Elevated SphK1 activity as well as upregulated S1P level is linked to various diseases, such as cancer, fibrosis and sickle cell disease. Therefore, there is a growing interest in studying on SphK1 as a potential target for the treatment of aforementioned diseases. Through high throughput screening, various SphK1 inhibitors have been discovered, among which PF 543 is the most potent inhibitor reported to date (Ki=3.6 nM). Previous research indicated that SphK1 inhibitor PF543 was effective in reducing S1P levels and slowing down the development process of sickle cell disease in vivo. However, the lack of in vivo stability of PF543 still makes it necessary to develop inhibitors with improved pharmacokinetic profile. In this study, PF543 was employed as the lead compound, and the influence of different tails groups upon binding affinity and in vivo stability were investigated. In brief, 28 compounds with different tail groups including alkyl, alkoxy, phenoxy and phenethyl groups were synthesized, and their inhibition potency were tested by broken-cell assay, with the hit compound being further evaluated on mice model for in vivo effect. Our preliminary results indicated that compounds SLL051666 and SLL05637 were the best two hits discovered so far, with the SphK1 inhibitions of 71% and 88%, respectively at 1 μM. Future study will focus on head group modification to improve in vivo stability.

Development of prolinol based derivatives targeting sphingosine kinase-1

254th National Meeting (2017)

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