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3-Deazaneplanocin A

MCE China：3-Deazaneplanocin A

Brand：MedChemExpress (MCE)

Cat. No.HY-10442

CAS：102052-95-9

Synonyms：DZNep; 3-Deazaneplanocin

Purity：99.80%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：3-Deazaneplanocin A (DZNep) is a potent histone methyltransferase EZH2 inhibitor. 3-Deazaneplanocin A is a potent S-adenosylhomocysteine hydrolase (AHCY) inhibitor. 3-Deazaneplanocin A shows anti-orthopoxvirus activity.

In Vitro：3-Deazaneplanocin A is a potent histone methyltransferase EZH2 inhibitor. Treatment of OCI-AML3 cells with 3-Deazaneplanocin A (1.0 μM) results in a significant increase in accumulation of cells in the G0/G1 phase (58.5%) with a concomitant decrease in the number of cells in S phase (35.2%) and G2/M phases (6.3%) of the cell cycle (P[1]. 3-Deazaneplanocin A reduces the expression of EZH2, especially after 72 hours (e.g. 48%, 32% and 36% reduction of EZH2 in PANC-1, MIA-PaCa-2 and LPc006 cells, respectively)[2]. 3-Deazaneplanocin A shows minimal growth inhibition in PANC-1 cells. More than 50% of these cells are still growing after exposure at the highest concentration (20 μM). MIA-PaCa-2 and LPc006 cells are much more sensitive, with IC0 values of 1±0.3 and 0.1±0.03 μM, respectively[2]. 3-Deazaneplanocin A causes dose-dependent inhibition of cell proliferation of NSCLC cell lines, and the IC0 values range from 0.08 to 0.24 μM[3].

In Vivo：The survival of NOD/SCID mice with acute myeloid leukemia (AML) due to HL-60 cells is significantly higher, if treated with 3-Deazaneplanocin A and Panobinostat (PS) compare to treatment with PS, 3-Deazaneplanocin A, or vehicle alone (P[1]. There is a progressive increase in weight of rats treated with physiological saline in a time-dependent manner (the mean growth rate=3.19% per day). Administration of 20 mg/kg 3-Deazaneplanocin A not only markedly reduces the relative weight of the rats compare to the initial weight (?2.0%, ?4.9% and ?1.2%) in the first three days post-treatment, but also suppresses the weight growth rate to 2.6% per day from the fourth day onwards post-dose[4].

Animal Administration：Mice[1] HL-60 cells (5 million) are injected into the tail vein of female nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and the mice are monitored for 7 days. The following treatments are administered in cohorts of 7 mice for each treatment: vehicle alone, 1 mg/kg 3-Deazaneplanocin A, 10 mg/kg PS, and 3-Deazaneplanocin A plus PS. Treatments are initiated on day 7. 3-Deazaneplanocin A is administered twice per week (Tuesday-Thursday) intraperitoneally for 2 weeks, and then discontinued. PS is administered 3 days per week (Monday, Wednesday, and Friday) for 4 weeks. The survival of mice from the tail vein model is represented with a Kaplan-Meier survival plot. Rats[4] Male wistar rats are used. The acute toxicity study is carried out to determine the NOAEL of 3-Deazaneplanocin A in rats. In total, 20 rats are divided into 4 groups of five each. Three groups are intravenously administered 20, 15, 10 mg/kg body weight (BW) 3-Deazaneplanocin A solution by the tail vein. The remaining group is given physiological saline (0.9% NaCl saline) as the control group. Then, the NOAEL of free 3-Deazaneplanocin A is determined, depending on the following endpoint parameters obtained.

Cell Assay：AML HL-60 cells are obtained and maintained. OCI-AML-3 cells are cultured in α minimum essential medium with 10% fetal bovine serum, 1% penicillin/streptomycin, and 1% nonessential amino acids. To analyze synergism between 3-Deazaneplanocin A and PS in inducing apoptosis, cells are treated with 3-Deazaneplanocin A (100-750 nM) and PS (5-20 nM) at a constant ratio for 48 hours. The percentage of apoptotic cells is determined by flow cytometry. The combination index (CI) for each drug combination is obtained by median dose effect of Chou and Talalay, using the CI equation within the commercially available software Calcusyn[1].

IC50 & Target：EZH2

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References：

[1]. Fiskus W, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood, 2009, 114(13), 2733-2743.  [Content Brief]

[2]. Avan A, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012 Aug;11(8):1735-46.  [Content Brief]

[3]. Kikuchi J, et al. Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. Lung Cancer. 2012 Nov;78(2):138-43.  [Content Brief]

[4]. Sun F, et al. Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus?. Eur J Pharm Sci. 2015 Sep 18;77:290-302.  [Content Brief]

[5]. Siddiqi FS, et al. The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes. J Am Soc Nephrol. 2016 Jul;27(7):2021-34.  [Content Brief]

[6]. Noriko Uchiyama, et al. Aristeromycin and DZNeP cause growth inhibition of prostate cancer via induction of mir-26a. Eur J Pharmacol. 2017 Oct 5;812:138-146.  [Content Brief]

[7]. Smee DF, et al. A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Res. 2003 Jan;57(1-2):41-52.  [Content Brief]