Spns2 (Sphingolipid Transporter 2) is a non-ATP dependent S1P (sphingosine-1-phosphate) transporter, that transports S1P from endothelial and lymph-endothelial cells, and regulates S1P concentration in plasma and lymph. Particularly, Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that is facilitated by Mfsd2b and spinster homologue 2 (Spns2). Importantly, Genetic studies in mice indicate that lymph S1P is primarily generated by Spns2-expressing endothelial cells lining the lymphatic vessels.

Besides, SPNS2 inhibits cell proliferation, migration, epithelial-mesenchymal transition (EMT), invasion, and metastasis in colorectal cancer (CRC) cell lines while silencing SPNS2 had the opposite effects. Additionally, SPNS2 leads to upregulation of PTEN and inactivation of Akt. Importantly, SPNS2 induces apoptosis in cancer cells. So, the inhibition of Spns2 might be a pharmaceutically viable method to direct highly localized reductions in fluid S1P concentrations.

SLF1081851 is a potent Spns2 inhibitor and inhibits S1P release.

SLF1081851 (0-5 μM; 18-20 h) inhibits S1P release with an IC₅₀ value of 1.93 μM in Hela cells. Besides, this compound (0-30 μM; 20 min) inhibits mSphK1 (recombinant mouse SphK) and mSphK2 in a dose-dependent manner with IC₅₀ values of ≥30 µM and ≈30 µM, respectively.

SLF1081851 plays a key role in modulating the immune system. SLF1081851 (20 mg/kg; i.p.) significantly decreases circulating lymphocyte counts and plasma S1P concentrations, recapitulating the genetic phenotype of Spns2 null mice. In addition, SLF1081851 (10 mg/kg; i.p.; once) shows a good pharmacokinetic profile, with a maximum concentration of 5 μM in blood at 2 h with drug levels sustained at ≥ 2 μM for at least 24 h, and a half-life of over 8 h in 4 weeks old Sprague-Dawley rats.

In a world, SLF1081851 is a potent Spns2 inhibitor and inhibits S1P release with an IC₅₀ value of 1.93 μM. Besides, SLF1081851 plays a key role in modulating the immune system.

Reference:

[1] Lv L, et al. Front Oncol. 2021 Jun 24;11:682773.
[2] Fritzemeier R, et al. J Med Chem. 2022 Jun 9;65(11):7656-7681.