SKI-178

• CAT Number: I009511
• CAS Number: 1259484-97-3
• Molecular Formula: C21H22N4O4
• Molecular Weight: 394.431
• Purity: ≥95%
• Synonyms: SKI-178; SKI 178; SKI178.;N/’-(1-(3,4-Dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide
• Target: SphK1 inhibitor
• Solubility: Soluble in DMSO
• Storage: 0 - 4 °C for short term, or -20 °C for long term
• IUPAC Name: N-[(E)-1-(3,4-dimethoxyphenyl)ethylideneamino]-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxamide
• InChI: InChI=1S/C21H22N4O4/c1-13(15-7-10-19(28-3)20(11-15)29-4)22-25-21(26)18-12-17(23-24-18)14-5-8-16(27-2)9-6-14/h5-12H,1-4H3,(H,23,24)(H,25,26)/b22-13+
• InChIKey: GMFUWEBOUKIKRP-LPYMAVHISA-N
• SMILES: CC(=NNC(=O)C1=CC(=NN1)C2=CC=C(C=C2)OC)C3=CC(=C(C=C3)OC)OC

SKI-178 (CAT: I009511) is indeed a sphingosine kinase 1 (SphK1) inhibitor, with an IC50 range of 0.1-1.8 μM. It induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. The sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the prosurvival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. SKI-178 shows promise as a novel therapeutic agent for the treatment of acute myeloid leukemia (AML), including multidrug-resistant/recurrent AML subtypes.

Reference

1:J Pharmacol Exp Ther. 2015 Mar;352(3):494-508. doi: 10.1124/jpet.114.219659. Epub 2015 Jan 6. The apoptotic mechanism of action of the sphingosine kinase 1 selective inhibitor SKI-178 in human acute myeloid leukemia cell lines.Dick TE,Hengst JA,Fox TE,Colledge AL,Kale VP,Sung SS,Sharma A,Amin S,Loughran TP Jr,Kester M,Wang HG,Yun JK, PMID: 25563902 PMCID: PMC4352591 DOI: 10.1124/jpet.114.219659 Abstract: We previously developed SKI-178 (N/’-[(1E)-1-(3,4-dimethoxyphenyl)ethylidene]-3-(4-methoxxyphenyl)-1H-pyrazole-5-carbohydrazide) as a novel sphingosine kinase-1 (SphK1) selective inhibitor and, herein, sought to determine the mechanism-of-action of SKI-178-induced cell death. Using human acute myeloid leukemia (AML) cell lines as a model, we present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. Further examination of the mechanism of action of SKI-178 implicated c-Jun NH2-terminal kinase (JNK) and cyclin-dependent protein kinase 1 (CDK1) as critical factors required for SKI-178-induced apoptosis. In cell cycle synchronized human AML cell lines, we demonstrate that entry into mitosis is required for apoptotic induction by SKI-178 and that CDK1, not JNK, is required for SKI-178-induced apoptosis. We further demonstrate that the sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the prosurvival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multidrug resistance mediated by multidrug-resistant protein1 and/or prosurvival Bcl-2 family member overexpression did not affect the sensitivity of AML cells to SKI-178. Taken together, these findings highlight the therapeutic potential of SKI-178 targeting SphK1 as a novel therapeutic agent for the treatment of AML, including multidrug-resistant/recurrent AML subtypes. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.