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SGI-1776 free base

MCE China：SGI-1776 free base

Brand：MedChemExpress (MCE)

Cat. No.HY-13287

CAS：1025065-69-3

Purity：99.23%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：SGI-1776 free base is an inhibitor of Pim kinases, with IC50s of 7 nM, 363 nM, and 69 nM for Pim-1, -2 and -3, respectively.

In Vitro：SGI-1776 free base (2.5, 5 μM) inhibits Pim-1 protein expression and Pim-1 kinase activity in SACC cells. SGI-1776 free base (2.5, 5 μM) causes cell cycle arrest and reduces cell proliferation in SACC-83 and SACC-LM cells[1]. SGI-1776 free base (5 μM) inhibits cell migration and invasiveness in both SACC-83 and SACC-LM cells. SGI-1776 free base (0, 2.5, or 5 μM) induces apoptosis via Caspase-3 activation[1]. SGI-1776 free base (5 µM) exerts inhibitory effects on both lipid accumulation and TG synthesis without affecting the number of adipocytes[2]. SGI-1776 free base (5 µM) inhibits adipogenesis particularly at an early phase of differentiation[2]. SGI-1776 free base (5 µM) decreases the expression of C/EBP-α and PPAR-γ and the phosphorylation levels of STAT-3 during adipocyte differentiation, and downregulates the protein and/or mRNA expression of FAS, leptin and RANTES during adipocyte differentiation[2]. SGI-1776 free base shows the significant activity against HO-8910 cells in a dose-dependent manner, with IC50 of (5.2±0.6) µM, and the inhibiting effect of SGI-1776 free base is sharply increased from 1.25 µM to 20 µM in vitro[3]. SGI-1776 free base inhibits the migration and invasion of HO-8910 cells in a dose-dependent manner, and the inhibiting migration and invasion rate of 5 µM[3]. SGI-1776 free base (2.5, 5 and 10 µM) decreases Pim-1 kinase activity of HO-8910 cells in a dose-dependent manner. Furthermore, the down-regulation of Pim-1 expression by SGI-1776 free base significantly inhibits cell viability, arrests cell in G1 phase, and inhibits the migration and invasion[3].

In Vivo：SGI-1776 free base (75, 200 mg/kg, p.o.) shows potent and sustained antitumor activity in a dose dependent manner in MV-4-11 xenografts in mice[4].

Animal Administration：The conditions for animal room environment and photoperiod are 20-25°C, 40%-70% humidity, and 12 hours of light/12 hours of dark cycle. Each mouse is inoculated subcutaneously at the right flank with MV-4-11 tumor cells (5×106). The treatments start when the tumor size reach 80-150 mm3. Mice are randomized to treatment groups based on their tumor sizes; tumor size is measured in 2 dimensions using a caliper, and the volume is expressed in mm3 using the formula: V = 0.5 a × b2 where a and b are the long and short diameters of the tumor, respectively. Pretreatment randomization ensures that each group has approximately the same mean tumor size. Mice are treated with vehicle (5% dextrose), SGI-1776 or cytarabine (ara-C). SGI-1776 and ara-C are formulated in 5% dextrose. SGI-1776 is administered by oral gavage (PO) on a daily × 5/week or twice/week schedule; ara-C is administered by intraperitoneal injection 3 times/week for 3 consecutive weeks. Animals are euthanized when their measured tumor size is greater than 3000 mm3 or when they lose ≥ 20% initial body weight; if the body weight loss ≥ 15%, treatment is stopped at first until mice regain body weight. Mice are euthanized when body weight loss is still ≥ 20% even after stopping treatment. T/C value (in %) is an indication of antitumor efficacy, where T and C are the mean tumor volume of the treated and control groups, respectively, on a given day. The differences between the mean tumor sizes for comparing groups is analyzed using the ANOVA test, where P ≤ 0.05 is considered to be statistically significant.

Cell Assay：Cells are seeded in a 96-well plate at a density of 5 000 cells/well. After incubation for 24 h, different concentrations of SGI-1776 (0.625, 1.25, 2.5, 5, 10, 20, 40 µM) are added to each well and cultured for 48 h. The medium is removed and then incubated with 5 mg/L MTT for 4 h. Next, the supernatant is removed after centrifugation. Finally, 100 µL of DMSO is added and an absorbance at 570 nm wavelength (A570) is measured by enzyme-labeling instrument. Relative cell proliferation inhibition rate (IR)=(1-average A570 of the experimental group/average A570 of the control group)×100%.

Kinase Assay：SACC-83 free base and SACC-LM cells of 0 μM, 2.5 μM and 5 μM groups after SGI-1776 exposure are harvested. 6 samples of SACC cells are diluted in Kinase buffer and pipetted into the wells which is pre-coated with a substrate corresponding to recombinant p21waf1. It contains threonine residues that can be efficiently phosphorylated by Pim-1. After undergoing the procedure, measure absorbance in each well is quantitated by spectrophotometry at dual wavelengths of 450/540 nm. It reflects the relative amount of Pim-1 activity in the 6 groups of SACC cells.

IC50 & Target：Ki: 7 nM (Pim-1), 363 nM (Pim-2), 69 nM (Pim-3)[4] Cellular Effect Cell Line Type Value Description References

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References：

[1]. Hou X, et al. Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776. Exp Cell Res. 2017 Mar 15;352(2):403-411.  [Content Brief]

[2]. Park YK, et al. The novel anti-adipogenic effect and mechanisms of action of SGI-1776, a Pim-specific inhibitor, in 3T3-L1 adipocytes. Int J Mol Med. 2016 Jan;37(1):157-64  [Content Brief]

[3]. Xie J, et al. SGI-1776, an imidazo pyridazine compound, inhibits the proliferation of ovarian cancer cells by inactivating Pim-1. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2014 Jul;39(7):649-57  [Content Brief]

[4]. Chen LS, et al. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood, 2011, 118(3), 693-702.  [Content Brief]