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SGI-1776 free base

Name: SGI-1776 free base
Brand: Selleck Chemicals
SKU: S2198
Rating: 5 (36 reviews)

Catalog No.S2198

For research use only.

SGI-1776 free base is a novel ATP competitive inhibitor of Pim1 with IC50 of 7 nM in a cell-free assay, 50- and 10-fold selective versus Pim2 and Pim3, also potent to Flt3 and haspin. SGI-1776 induces apoptosis and autophagy. Phase 1.

CAS No. 1025065-69-3

Selleck's SGI-1776 free base has been cited by 36 publications

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Pim Signaling Pathway Map

Biological Activity

Description

Targets

Pim1 ^[1] (Cell-free assay)	FLT3 ^[1] (Cell-free assay)	Pim3 ^[1] (Cell-free assay)	Pim2 ^[1] (Cell-free assay)
7 nM	44 nM	69 nM	363 nM

In vitro

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. ^[1]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. ^[2] 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. ^[3]

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Formulation	Activity Description	PMID

CHO cells	M33mXGZ2dmO2aX;uJIF{e2G7				M4\oemlvcGmkaYTpc44hd2ZiaIXtZY4hTVKJIHX4dJJme3OnZDDpckBEUE9iY3XscJMh[nliYYX0c41ifGWmIIDheINpKGOuYX3wJI1mfGixZDygTWM2OD1zIN88US=>	NUT2dnNUOjV3OEm5N\|I>

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Assay

Methods	Test Index	PMID

Western blot

c-Myc (Ser62) / c-Myc / p-Histone H3 (Ser10) / Histone H3 / Bad(Ser112) / Bad / 4E-BP1 ; Mcl-1 ; Cell viability ; p70-S6K / p-P70S6K / rpS6 / p-rpS6

22955922 22015557 27120806

In vivo

Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors shows efficacy with SGI-1776. ^[1] 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. ^[3]

Protocol (from reference)

Kinase Assay:^[2]	Kinase Assays: 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 Research:^[1]	Cell lines: MV-4-11, MOLM-13, and OCI-AML-3 cell lines Concentrations: 0.1-10 μM Incubation Time: 24 hours Method: Cells are cultured in IMDM (ATCC) supplemented with 10% FBS and grown in a 37^oC 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.
Animal Research:^[1]	Animal Models: Female cNOD-SCID mice Dosages: 75 mg/kg and 200 mg/kg Administration: Administered via oral gavage (PO) on a daily ×5/week or twice/week schedu

References

Solubility (25°C)

In vitro


In vivo	Add solvents to the product individually and in order (Data is from Selleck tests instead of citations): 30% propylene glycol, 5% Tween 80, 65% D5W For best results, use promptly after mixing. Click to purchase: Tween 80	30 mg/mL

Chemical Information

Molecular Weight	405.42
Formula	C₂₀H₂₂F₃N₅O
CAS No.	1025065-69-3
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2

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