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|Solubility (25°C) *||In vitro||DMSO||13 mg/mL (41.36 mM)|
|In vivo||0.5% CMC||5 mg/mL|
* <1 mg/ml means slightly soluble or insoluble.
* 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.
|Description||MC1568 is a selective HDAC inhibitor for maize HD1-A with IC50 of 100 nM in a cell-free assay. It is 34-fold more selective for HD1-A than HD1-B.|
|In vitro||MC1568 is a selective class II (IIa) histone deacetylas (HDAC II) inhibitor with IC50 of 220 nM and 176-fold class II selectivity (against class I). In human breast cancer ZR-75.1 cell lysates, MC1568 (5 μM) shows no inhibitory activity against HDAC1 but is able to inhibit HDAC4.  In MCF-7 cells, MC1568 (20 μM) increases the accumulation of acetylated H3 and H4 histones, as well as the levels of acetyl-tubulin, which indicates a inhibitory effect of MC1568 on HDAC6.  In C2C12 cells, MC1568 (5 μM) arrests myogenesis by decreasing myocyte enhancer factor 2D (MEF2D) expression, stabilizing the HDAC4-HDAC3-MEF2D complex, and by inhibiting differentiation-induced MEF2D acetylation.  MC1568 (5 or 10 μM) interferes with the RAR- and PPARγ-mediated differentiation-inducing signaling pathways. In F9 cells, MC1568 specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis. |
|In vivo||In mice, MC1568 (50 mg/kg) shows an apparent tissue-selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a repressed state.  In reporting PPRE-Luc mice, MC1568 (50 mg/kg) impairs PPARγ signaling mostly in the heart and adipose tissues.  In a recent study of pancreatic explants, MC1568 enhances expression of Pax4, a key factor required for proper β-and δ-cell differentiation and amplifies endocrine β- and δ-cells. |
|Maize HD2, HD1-B, and HD1-A Enzyme Inhibition.||The enzyme liberats tritiated acetic acid from the substrate, which is quantified by scintillation counting. IC50 values are results of triple determinations. A 50 μL sample of maize enzyme (at 30 °C) is incubated (30 min) with 10 μL of total [3H]acetate-prelabeled chicken reticulocyte histones (2 mg/mL). Reaction is stopped by addition of 50 μL of 1 M HCl/0.4 M acetate and 800 μL of ethyl acetate. After centrifugation (1×104 g, 5 min), an aliquot of 600 μL of the upper phase is counted for radioactivity in 3 mL of liquid scintillation cocktail. MC1568 is tested at a starting concentration of 40 μM, and active substances are diluted further. NaB, VPA, TSA, SAHA, 85 TPX, HC-toxin, and tubacin are used as the reference compounds, and blank solvents are used as negative controls.|
|Cell lines||3T3-L1 cells|
|Concentrations||~10 μM, dissolved in DMSO|
|Incubation Time||8 days|
|Method||The 3T3-L1 cells are propagated and differentiated using a cocktail of isobutylmethylxanthine, dexamethasone, and insulin. From the second day post-confluence and throughout the differentiation period of 8 days, the 3T3-L1 cells are induced by: (1) no induction: at post-confluence and throughout the differentiation period of 8 days, the cells are incubated with DMSO or MC1568. (2) troglitazone: at post-confluence and throughout the differentiation period of 8 days, the cells are induced with 5 μM troglitazone, MC1568, or both. (3) rosiglitazone: at post-confluence and throughout the differentiation period of 8 days, the cells are incubated with 1 μM rosiglitazone and either DMSO or MC1568. (4) rosiglitazone and dexamethasone: at post-confluence, the cells received 1 μM of rosiglitazone and 390 ng/mL dexamethasone. Throughout the differentiation period of 8 days, the cells are induced with 1 μM of rosiglitazone and either DMSO or MC1568. All medium is renewed every second day.|
|Animal Models||PPRE-Luc transgenic mouse (C57BL/6)|
|Formulation||Dissolved in water solution of 0.5% carbossimetilcellulose|
|Administration||By gavage once a day|
Data from [Proc Natl Acad Sci U S A, 2012, 109(34)]
HDAC4 and OA1 expression correlate inversely during starvation, and HDAC4 inhibition or knockdown leads to OA1 transgene up-regulation. Quantification of OA1 mRNA expression by real-time PCR in HeLa-OA1myc cells at the indicated times of incubation with MC1568 (class II HDACi). Data are expressed as the fold change compared with the amount of the OA1 mRNA in mock conditions at each time point.
Data from [Proc Natl Acad Sci U S A, 2012, 109(34)]
HDAC4 is down-regulated during starvation, and its inhibition leads to HIV-1 reactivation in ACH-2 cells. (B) Real-time PCR quantification of US HIV-1 RNA in ACH-2 cells incubated with DMSO (mock of MC1568), MC1568, or TSA at the reported times…(D) 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell viability and proliferation of daily collected supernatants from ACH-2 cells incubated for 3 d.
Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease. [Ueki N, et al. Nat Commun, 2013, 4:2735]PubMed: 24193185
Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4). [Palmisano I, et al. Proc Natl Acad Sci USA, 2012, 109(34):E2284-93]PubMed: 22826225
Identifying targets for the restoration and reactivation of BRM. [Kahali B, et al. Oncogene, 2014, 33(5):653-64]PubMed: 23524580
Epigenetic mechanisms linking diabetes and synaptic impairments. [Wang J, et al. Diabetes, 2013, 63(2):645-54]PubMed: 24154559
HDAC4 mediates IFN-γ induced disruption of energy expenditure-related gene expression by repressing SIRT1 transcription in skeletal muscle cells [Fang M, et al. Biochim Biophys Acta, 2016, 1859(2):294-305]PubMed: 26619800
AMP-activated protein kinase α1 but not α2 catalytic subunit potentiates myogenin expression and myogenesis. [Fu X, et al. Mol Cell Biol, 2013, 33(22):4517-25]PubMed: 24043309
An "Exacerbate-reverse" strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease. [Munkacsi AB, et al. J Biol Chem, 2011, 286(27):23842-51]PubMed: 21489983
Suberoylanilide hydroxamic acid (Vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. [Cenik B, et al. J Biol Chem, 2011, 286(18):16101-8]PubMed: 21454553
Inhibition of Multiple Pathogenic Pathways by Histone Deacetylase Inhibitor SAHA in a Corneal Alkali-Burn Injury Model. [Li X, et al. Mol Pharm, 2013, 10(1):307-18]PubMed: 23186311
Chromatin-Remodeling Factors Mediate the Balance of Sense-Antisense Transcription at the FGF2 Locus. [McEachern LA Mol Endocrinol, 2014, 28(4):477-89]PubMed: 24552587
Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling [Sinnett-Smith J, et al Am J Physiol Cell Physiol, 2014, 306(10):C961-71]PubMed: 24647541
Toxoplasma gondii inhibits IFN-γ- and IFN-β-induced host cell STAT1 transcriptional activity by increasing the association of STAT1 with DNA. [Rosowski EE, et al. Infect Immun, 2013, 82(2):706-19]PubMed: 24478085
Natural indoles, indole-3-carbinol and 3,3'-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. [Busbee PB, et al. Toxicol Appl Pharmacol, 2014, 274(1):7-18]PubMed: 24200994
Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer. [Wang G, et al. PLoS One, 2012, 7(12):e52095]PubMed: 23251689
Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle. [Lemon DD, et al. FEBS Lett, 2015, 589(10):1080-8]PubMed: 25816750
Inhibition of Histone Deacetylase 4 Increases Cytotoxicity of Docetaxel in Gastric Cancer Cells [Colarossi L, et al Proteomics Clin Appl, 2014, 8(11-12):924-31]PubMed: 25091122
Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT). [Carrillo AK, et al. Bioorg Med Chem, 2015, 10.1016/j.bmc.2014.12.066]PubMed: 25637120
Inhibition of histone deacetylases stimulates HBV replication independent of protein X. [Klundert MA, et al. Future Virol, 2015, 10(4), 351–356]
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