SKI-178 is a sphingosine kinase 1 (SphK1) inhibitor (IC50 = 0.1-1.8 μM) which is a novel therapeutic agent for the treatment of AML, including multidrug-resistant/recurrent AML subtypes.
Physicochemical Properties
| Molecular Formula | C21H22N4O4 |
| Molecular Weight | 394.431 |
| Exact Mass | 394.164 |
| Elemental Analysis | C, 63.95; H, 5.62; N, 14.20; O, 16.22 |
| CAS # | 1259484-97-3 |
| PubChem CID | 5342941 |
| Appearance | White to off-white solid powder |
| LogP | 3.647 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 29 |
| Complexity | 565 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O(C)C1=C(C=CC(=C1)C(C)=NNC(C1=CC(C2C=CC(=CC=2)OC)=NN1)=O)OC |
| InChi Key | GMFUWEBOUKIKRP-LPYMAVHISA-N |
| InChi Code | 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+ |
| Chemical Name | N'-(1-(3,4-Dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide InChi Key |
| Synonyms | SKI 178 SKI-178 SKI178. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Prolonged Bcl-2 phosphorylation is linked to liver cancer cell mortality mediated by SKI-178 (5 μM; 24 hours) [1]. |
| ln Vivo | In the MLL-AF9 model, SKI-178 (20 mg/kg; injected behind the eyelid under isoflurane anesthesia) prevents leukemia from progressing [3]. |
| Cell Assay |
Apoptosis analysis [1] Cell Types: HL-60 cells Tested Concentrations: 5 μM Incubation Duration: 24 hour Experimental Results: JNK activity (expressed as Thr183/Tyr185 phosphorylation) increased in a time-dependent manner, starting as early as 2 hrs (hours) and continuing to increase At least 24 hrs (hours). Cleavage of caspase-7 indicates a concomitant increase in apoptotic cell death. Bcl-2 Ser70 phosphorylation increased with time of SKI-178 treatment, reaching maximum levels at 8 hrs (hours), consistent with the time of caspase-7 activation. |
| Animal Protocol |
Animal/Disease Models: MLL-AF9 mouse model (leukemia mouse) [3] Doses: 20 mg/kg Route of Administration: Retroorbital injection under isoflurane anesthesia; 3 times a week for 1 and 3 weeks Experimental Results: White blood cells (WBC) counts diminished from an initial level of 104 cells/μL and continued to decrease after 3 weeks of treatment until reaching normal levels (~4 × 103 cells/μL). |
| References |
[1]. 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]. Development of a sphingosine kinase 1 specific small-molecule inhibitor. Bioorg Med Chem Lett. 2010;20(24):7498-7502. [3]. 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. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~126.77 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.34 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5353 mL | 12.6765 mL | 25.3530 mL | |
| 5 mM | 0.5071 mL | 2.5353 mL | 5.0706 mL | |
| 10 mM | 0.2535 mL | 1.2677 mL | 2.5353 mL |