UNC0321
目录号 : GC37856
A highly potent inhibitor of G9a histone methyltransferase
Cas No.:1238673-32-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
The methylation of lysine residues on histones plays a central role in determining euchromatin structure and gene expression. The histone methyltransferase (HMTase) G9a can mono-
1.Tachibana, M., Sugimoto, K., Nozaki, M., et al.G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesisGenes Dev.16(14)1779-1791(2002) 2.Wagschal, A., Sutherland, H.G., Woodfine, K., et al.G9a histone methyltransferase contributes to imprinting in the mouse placentaMol. Cell Biol.28(3)1104-1113(2008) 3.Thomas, L.R., Miyashita, H., Cobb, R.M., et al.Functional analysis of histone methyltransferase G9a in B and T lymphocytesJ. Immunol.181(1)485-493(2008) 4.Liu, F., Chen, X., Allali-Hassani, A., et al.Protein lysine methyltransferase G9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolinesJ. Med. Chem.53(15)5844-5857(2010)
| Cas No. | 1238673-32-9 | SDF | |
| Canonical SMILES | CN1CCC(NC2=C3C=C(OC)C(OCCOCCN(C)C)=CC3=NC(N4CCN(C)CCC4)=N2)CC1 | ||
| 分子式 | C27H45N7O3 | 分子量 | 515.69 |
| 溶解度 | DMSO: ≥ 31 mg/mL (60.11 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9391 mL | 9.6957 mL | 19.3915 mL |
| 5 mM | 0.3878 mL | 1.9391 mL | 3.8783 mL |
| 10 mM | 0.1939 mL | 0.9696 mL | 1.9391 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
UNC0321 inhibits high glucose induced apoptosis in HUVEC by targeting Rab4
Biomed Pharmacother 2020 Nov;131:110662.PMID:32877824DOI:10.1016/j.biopha.2020.110662.
The vascular complications in heart, brain, kidney and retina are the most common chronic complications of diabetes mellitus (DM). At present, it has become a research hotspot to regulate the abnormal apoptosis of vascular endothelial cells for DM treatment. UNC0321 is a high affinity GPCRs inhibitor, and has potential practical value in chromatin remodeling. In this study, we treated HUVEC with UNC0321 in vitro, and found that UNC0321 inhibit the level of Cleaved-Caspase3 and Bax, thus inhibiting the apoptosis caused by high glucose. In addition, UNC0321 also promoted cell proliferation and migration by activating Akt / mTOR pathway. The transcriptome changes of HUVEC cells cultured with high glucose with or without the treatment of UNC0321 were analysis using sequencing. It was found that Rab4 expression was significantly inhibited after UNC0321 treatment. Subsequently, we overexpressed Rab4 in HUVEC cells cultured with high glucose, and found that overexpression of Rab4 promoted the apoptosis, and inhibited cell proliferation and migration. At the same time, after overexpression of Rab4 in HUVEC cells treated with UNC0321, the number of apoptosis was significantly increased, cell proliferation and migration were inhibited, and the activity of Akt / mTOR pathway decreased. These data suggested that overexpression of Rab4 effectively blocked the inhibition of apoptosis and the increase of cell proliferation induced by UNC0321. In conclusion, we found that UNC0321 inhibits the apoptosis of HUVEC cells caused by high glucose through inhibiting Rab4 expression, providing new potential drugs and targets for the treatment of diabetic vascular complications.
Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines
J Med Chem 2011 Sep 8;54(17):6139-50.PMID:21780790DOI:10.1021/jm200903z.
Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.
Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines
J Med Chem 2010 Aug 12;53(15):5844-57.PMID:20614940DOI:10.1021/jm100478y.
Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.