LAQ824 (Dacinostat) 404951-53-7

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Molecular Weight:

379.459 LAQ824 (Dacinostat) is a novel HDAC Inhibitor with IC50 of 32 nM and is known to activate the p21 promoter.






Biological Activity


LAQ824 activates the expression of the gene encoding the p21 Cell Cycle
inhibitor by activating the p21 promoter with 50% of the maximal
promoter activation (AC50) of 0.30 μM. LAQ824 inhibits the cell growth
of both H1299, a non-small cell lung carcinoma line, and HCT116, a colon
cancer cell line with IC50 of 0.15 μM and 0.01 μM, respectively, and
the antiproliferative effect of LAQ824 is selective toward the tumor
cell lines while inducing only growth arrest in normal fibroblasts.


Furthermore, LAQ824 induces a dose-dependent increase of p21 protein in
A549 cells and an increase in the hypophosphorylated state of the Rb
tumor suppressor. A recent study shows that LAQ824
induces chromatin changes at the level of the IL-10 gene promoter that
lead to enhanced recruitment of the transcriptional repressors HDAC11
and PU.1 and inhibits IL-10 production in BALB/c murine macrophages.


In HCT116 and human colon tumor xenografts in nude mice, LAQ824
treatment at 100 mg/kg produces the inhibitory effects on tumor growth
in a dose-dependent mode without general cytotoxicity.






In Vitro Histone Deacetylase Assay


HDAC enzymes are partially purified from H1299 cell lysate by ion
exchange chromatography using the Q Sepharose Fast Flow column. Enzyme
complexes are collected from 500 mg of total cell lysate by
immunoprecipitation with cdk2 polyclonal antibody or cdk1/cdc2
monoclonal antibody.


Immunoprecipitates are resuspended in kinase buffer
(50 mM Hepes, pH 8, 10 mM MgCl2, 2.5 mM EDTA, 1 mM dithiothreitol, 20 mM ATP, 10 mM β-glycerophosphate, 0.1 mM NaVO4, 1 mM sodium fluoride, 50 mM ATP, 10 μCi of [γ-32P]ATP)
along with 1 μg of pRb recombinant protein substrate (cdk2) or 10 mL of
H1 histone mixture containing 20 μg of substrate (cdc2). Phosphorylated
Rb and H1 histone are resolved by electrophoresis and quantitated using
a PhosphorImager.




Method


Cell
proliferation is measured using an adaptation of published procedures
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium
assay). The cells are seeded in 12-well dishes and cultured in RPMI
1640 containing 10% FBS. The cells are cultured in the presence of
various concentrations of TSA (up to 1,000 ng/mL). To examine the growth
inhibition by TSA, viable cell numbers are determined by trypan blue
dye exclusion, counted in a Nesbauer-type hemocytometer for 0 hour, 24
hours, and 48 hours.


The same amount of ethanol is added to the RPMI
1640 medium as the control experiment. All experiments are performed in
duplicate and repeated 3 times The average background value (treatment
with medium alone) is subtracted from each experimental well; triplicate
values are averaged for each compound dilution.


The following formulas
are used to calculate the percentage of growth: If X0, %Growth=(X-T0)/T0*100; If X>T0, %Growth=(X-T0)/(GC-T0)*100. where T0 is the average value of T0 − background, GC is the average value of untreated cells (in
triplicate) − background, and X is the average value of compound-treated
cells (in triplicate)-background. The [% Growth" is plotted against
compound concentration and used to calculate the IC50 using the linear
regression techniques between data points to predict the concentration
of compounds at 50% inhibition.

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Product Categories : Epigenetics > HDAC Inhibitor