SKI-178

SKI-178 is a potent sphingosine kinase-1 (SphK1) and SphK2 inhibitor. SKI-178 is cytotoxic at IC50 concentrations ranging from 1.8 to 0.1 μM in both drug sensitive and multi-drug resistant cancer cell lines (i.e., MTR3, NCI-ADR and HL60/VCR). SKI-178 induces apoptosis in a CDK1-dependent manner in human acute myeloid leukemia cell lines[1][2].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> SPHK

SKI-178 (5 μM; 24 hours)-induced apoptotic cell death correlates with prolonged Bcl-2 phosphorylation[1]. Apoptosis Analysis[1] Cell Line: HL-60 cells Concentration: 5 μM Incubation Time: 24 hours Result: JNK activity (indicated by phosphorylation at Thr183/Tyr185) increased in a time-dependent manner starting as early as 2 hours continued to increase for at least 24 hours. There was a concomitant increase in apoptotic cell death indicated by the cleavage of caspase-7. Bcl-2 phosphorylation at Ser70 increased with time in response to SKI-178 treatment, reaching maximal levels at 8 hours, which was consistent with the timing of caspase-7 activation.

SKI-178 (20mg/kg; retro-orbital injection under isoflurane anesthesia) inhibits leukemic progression in the MLL-AF9 model[3]. Animal Model: MLL-AF9 mouse model (leukemic mice)[3] Dosage: 20 mg/kg Administration: Retro-orbital injection under isoflurane anesthesia; three times per week for 1 and 3 weeks Result: White blood cell (WBC) counts decreased from their initial 104 cells/μL levels and continued to decline after 3 weeks of treatment until they reached normal levels (~4×103 cells/μL).

[1]. Hengst JA, et al. SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models. Cancer Transl Med. 2017;3(4):109-121.

[2]. Hengst JA, et al. Development of a sphingosine kinase 1 specific small-molecule inhibitor. Bioorg Med Chem Lett. 2010;20(24):7498-7502.

[3]. Dick TE, et al. The apoptotic mechanism of action of the sphingosine kinase 1 selective inhibitor SKI-178 in human acute myeloid leukemia cell lines. J Pharmacol Exp Ther. 2015;352(3):494-508.