SGI-1776 free base 1025065-69-3

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Molecular Weight:

405.42 SGI-1776 is a novel ATP competitive inhibitor of Pim1 with IC50 of 7 nM, 50- and 10-fold selective versus Pim2 and Pim3, also potent to Flt3 and haspin. Phase 1.


Biological 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.


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.






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.


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.

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