CAS NO: | 438190-29-5 |
规格: | ≥98% |
包装 | 价格(元) |
5mg | 电议 |
10mg | 电议 |
25mg | 电议 |
50mg | 电议 |
100mg | 电议 |
250mg | 电议 |
500mg | 电议 |
1g | 电议 |
Molecular Weight (MW) | 273.23 |
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Formula | C11H6F3NO2S |
CAS No. | 438190-29-5; |
Storage | -20℃ for 3 years in powder form |
-80℃ for 2 years in solvent | |
Solubility (In vitro) | DMSO: 10 mM in DMSO |
Water: <1 mg/mL | |
Ethanol: N/A | |
SMILES Code | O=C(NC/1=O)SC1=C\C2=CC=CC(C(F)(F)F)=C2 |
Synonyms | TCS PIM-1 4a; SMI-4a; SMI4a; SMI 4a Chemical Name: 5-(3-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione InChi Key: NGJLOFCOEOHFKQ-VMPITWQZSA-N InChi Code: InChI=1S/C11H6F3NO2S/c12-11(13,14)7-3-1-2-6(4-7)5-8-9(16)15-10(17)18-8/h1-5H,(H,15,16,17)/b8-5+ |
In Vitro | In vitro activity: SMI-4a is a novel benzylidene-thiazolidine-2, 4-dione small molecule, potent and selective inhibitor of Pim1 with IC50 of 17 nM, it is modestly potent to Pim-2, and does not significantly inhibit any other serine/threonine- or tyrosine-kinases. SMI-4a blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2). The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. SMI-4a kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. These data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL. SMI-4a is an ATP competitive inhibitor of Pim1 with IC50 of 17 nM. SMI-4a shows high selectivity for Pim1 against a panel of kinases. SMI-4a inhibits the in vitro phosphorylation by Pim-1 of the known substrate, the translational repressor 4E-BP1. SMI-4a (5μM) inhibits pancreatic and leukemic cells growth. SMI-4a reduces phosphorylation of the Pim target Bad in prostate and hematopoietic cells. SMI-4a causes cell cycle arrest and reverses the antiapoptotic activity of Pim-1. SMI-4a increases the amount of p27Kip1 in the nucleus. SMI-4a treatment of pre-T-LBL inhibits the mTOR pathway. SMI-4a reduces MYC protein expression in pre-T-LBL. SMI-4a treatment induces up-regulation of MAPK pathway Kinase Assay: SMI-4a is a selective ATP-competitive Pim-1 kinase inhibitor with an IC50 of 21 nM for Pim-1 compared to an IC50 of 100 nM for Pim-2 and with little or no activity against a panel of 50 other kinases tested. Cell Assay: 6812/2 cells were incubated for 24 hours and Jurkat cells, for 48 hours with SMI-4a (10μM) or dimethyl sulfoxide (DMSO) in serum-free medium. After incubation, cells were harvested, washed once in phosphate-buffered saline (PBS), fixed in cold 70% ethanol for 45 minutes, stained with propidium iodide solution that contains RNaseA for 30 minutes, and analyzed by flow cytometry. |
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In Vivo | SMI-4a (60 mg/Kg) treatment twice daily significantly reduce tumor size and is well tolerated. Tumors harvested 1 hour after the final oral gavage of SMI-4a demonstrates decreased phosphorylation of p70 S6K compared with tumors from mice treated with vehicle, whereas in comparison total p70 S6K expression isunchanged. |
Animal model | Nu/nu nude mice injected with pre-T-LBL cells |
Formulation & Dosage | Dissolved in 65% DMSO, 30% PEG-400, 5% Tween-80; 75, 60 mg/kg; oral administration |
References | Mol Cancer Ther. 2009 Jun;8(6):1473-83; Blood. 2010 Jan 28;115(4):824-33. |