product name SGI-1776 free base
Description: SGI-1776 free base is a novel ATP competitive inhibitor of the serine/threonine family of Pim kinase, an enzyme regulating cell survival. It has an IC50 of 7 nM in a cell-free assay, and is 50- and 10-fold selective versus Pim2 and Pim3, also potent to Flt3 and haspin. Through extensive biomedical characterization, SGI-1776 exhibits specificity to the three isoforms of the Pim family, including Pim-1, Pim-2, and Pim-3.
References: Blood. 2011 Jul 21;118(3):693-702; Pediatr Blood Cancer. 2012 Oct;59(4):749-52.
405.42
Formula
C20H22F3N5O
CAS No.
1025065-69-3
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 81 mg/mL (199.8 mM)
Water: <1 mg/mL
Ethanol: 81 mg/mL (199.8 mM)
Solubility (In vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: In addition to Pim, SGI-1776 also potently targets FLT3 (IC50 = 44nM). Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis. Importantly, SGI-1776 is also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and results in Mcl-1 protein decline. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction. Apoptosis induction coupled with the inhibition of RNA synthesis is observed in CLL cells treated with SGI-1776. SGI-1776 exhibites cytotoxic activity in vitro with a median relative IC50 of 3.1 mM. SGI-1776 induces tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induces complete responses of subcutaneous MV4;11. Kinase Assay: Kinase inhibition is measured by the use of radiometric assays performed by KinaseProfiler service. Assays contain a peptide substrate, known purified recombinant human kinases, gamma-labeled ATP, magnesium ion, and a fixed concentration (1 μM) of SGI-1776. In a final reaction volume of 25 μL, 5 to 10 mU of Pim1/2/3 is incubated with 8 mM of MOPS, pH 7.0; 0.2 mM ethylene diamine tetraacetic acid; 100 μM KKRNRTLTV;10 mM MgAcetate; and [γ-32P-ATP] . The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 μL of a 3% phosphoric acid solution. Then, 10 μL of the reaction is spotted onto a P30 filtermat and washed 3 times for 5 minutes in 75 mM phosphoric acid and once in methanol before it is dried and measured via a scintillation counter. Cell Assay: Cells (MV-4-11, MOLM-13, and OCI-AML-3 cell lines) are cultured in IMDM (ATCC) supplemented with 10% FBS and grown in a 37oC incubator with 5% CO2. Cells are routinely tested for Mycoplasma infection using a commercially available kit. Cells are treated with DMSO or various concentrations of SGI-1776 for 24 hours. Cells (1×106) are washed, then resuspended in 100 μL of annexin binding buffer, mixed with 5 μL of FITC solution and 5 μL of propidium iodide (PI; 50 μg/mL) solution. For each sample, 1×104 cells are measured using a Becton Dickinson FACSCalibur flow cytometer |
|---|---|
| In Vivo | Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors shows efficacy with SGI-1776. SGI-1776 has shown preclinical activity against leukemia and solid tumor cell line models with IC50 values of 0.005–11.68 mM. SGI-1776 induces significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. |
| Animal model | Female cNOD-SCID mice |
| Formulation & Dosage | Dissolved in 5% dextrose; 75, 200 mg/kg; oral administration |
| References | Blood. 2011 Jul 21;118(3):693-702; Pediatr Blood Cancer. 2012 Oct;59(4):749-52. |
