LAQ824 (NVP-LAQ824) is a potent novel histone deacetylase (HDAC) inhibitor with an IC50 of 0.032 μM. NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage.
|Cell lines||HCT116, H1299, PC-3, DU145 and MDA435 cells|
|Preparation method||Monolayer Growth Inhibition Assay. Cell proliferation was measured using an adaptation of published procedures (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium assay) as described previously (29) . The CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay was performed according to the manufacturer’s protocol. The average background value (treatment with medium alone) was subtracted from each experimental well; triplicate values were averaged for each compound dilution. The following formulas were used to calculate the percentage of growth: The “% Growth” was 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.|
|Incubation time||72 hr|
|Animal models||HCT116 cells tumor-bearing mice|
|Formulation||dissolved in DMSO to create a stock solution, which was further diluted just before dosing with D5W to a final DMSO concentration of 10%.|
|Dosages||once daily, 5 days/week, for a total of 15 doses.|
|Administration||i.v. injection into the tail vein|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Histone deacetylase inhibition increases levels of choline kinase α and phosphocholine facilitating noninvasive imaging in human cancers.
Beloueche-Babari M et al. Cancer Res. 2012 Feb 15;72(4):990-1000. PMID: 22194463.
Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10.
Wang H et al. J Immunol. 2011 Apr 1;186(7):3986-96. PMID: 21368229.
The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells.
Schwarz K et al. Leuk Res. 2011 Jan;35(1):119-25. PMID: 20674020.
Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824).
Cho YS et al. J Med Chem. 2010 Apr 8;53(7):2952-63. PMID: 20205394.
Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824.
Vo DD et al. Cancer Res. 2009 Nov 15;69(22):8693-9. PMID: 19861533.
The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy.
Ellis L et al. Blood. 2009 Jul 9;114(2):380-93. PMID: 19383971.
Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824.
Atadja P, et al. Cancer Res. 2004 Jan 15;64(2):689-95. PMID: 14744786.
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Sodium butyrate is the sodium salt of butyric acid, which has been reported to cause hyperacetylation of histones due to its role as a HDAC inhibitor with IC50 values of 0.3, 0.4, 0.3 mM for HDAC1, 2 and 7 respectively.
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