SGI-1776 free base

For research use only.

Catalog No.S2198

33 publications

SGI-1776 free base Chemical Structure

CAS No. 1025065-69-3

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.

Selleck's SGI-1776 free base has been cited by 33 publications

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Biological Activity

Description 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.
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 NHrvVHdHfW6ldHnvckBie3OjeR?= MXLJcohq[mm2aX;uJI9nKGi3bXHuJGVTTyCneIDy[ZN{\WRiaX6gR2hQKGOnbHzzJIJ6KGG3dH;tZZRm\CCyYYTjbEBkdGGvcDDt[ZRpd2RuIFnDOVA:OSEQvF2= M3;RSFI2PTh7OUOy

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
c-Myc (Ser62) / c-Myc / p-Histone H3 (Ser10) / Histone H3 / Bad(Ser112) / Bad / 4E-BP1 ; 

PubMed: 22955922     


Effect of SGI-1776 on phospho-c-Myc (Ser62) and total c-Myc (A) phospho-Histone H3 (Ser10) and total Histone H3 (B), phospho-Bad (Ser112) and total Bad (C), and phospho-4E-BP1(Thr37/46) and total 4E-BP1 (D) protein expressions. JeKo-1 and Mino cell were treated with 0.1, 1, 3, 5, or 10μM SGI-1776 for 24 hours, and then cell lysates were analyzed via immunoblot. 

Mcl-1; 

PubMed: 22955922     


Impact of SGI-1776 in dose-dependent (E) treatments on Mcl-1 protein expression in JeKo-1 and Mino cells. Mcl-1 protein expression was measured by immunoblots.

Cell viability ; 

PubMed: 22015557     


SGI-1776 reduces RCC cell viability. Five RCC cell lines and RPTEC cells were incubated with the indicated concentrations of SGI-1776 for 72 h and cell viability was measured by MTT assay. Mean±s.d., n=3.

p70-S6K / p-P70S6K / rpS6 / p-rpS6 ; 

PubMed: 27120806     


LN229 cells were treated with SGI-1776 (5 μM) for the indicated times. Equal amounts of total cell lysates were subjected to SDS-PAGE followed by immunoblotting with antibodies against the phosphorylated forms of p70-S6K (pThr389), rpS6 (pSer235/236), or against HSP90 as indicated. Equal amounts of cell lysates from the same experiment were analyzed in parallel by SDS-PAGE and immunoblotted with antibodies against p70-S6K or rpS6, as indicated. 

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

Kinase Assay:[2]
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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]
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  • 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 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.
    (Only for Reference)
Animal Research:[1]
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  • 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
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 81 mg/mL (199.79 mM)
Water Insoluble
Ethanol '81 mg/mL
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. 		30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 405.42
Formula

C20H22F3N5O
CAS No. 1025065-69-3
Storage powder
in solvent
Synonyms N/A
Smiles CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Pim Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID