7-[2-[2-(二甲基氨基)乙氧基]乙氧基]-2-(六氢-4-甲基-1H-1,4-二氮杂卓-1-基)-6-甲氧基-N-(1-甲基-4-哌啶基)-4-喹唑啉胺 | 1238673-32-9

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 7-[2-[2-(二甲基氨基)乙氧基]乙氧基]-2-(六氢-4-甲基-1H-1,4-二氮杂卓-1-基)-6-甲氧基-N-(1-甲基-4-哌啶基)-4-喹唑啉胺
• 中文别名: G9A抑制剂(UNC0321)
• 英文名称: 7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine
• 英文别名: UNC0321；7-[2-[2-(dimethylamino)ethoxy]ethoxy]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine
• CAS: 1238673-32-9
• 化学式: C₂₇H₄₅N₇O₃
• 分子量: 515.699
• InChiKey: AULLUGALUBVBDD-UHFFFAOYSA-N

物化性质

• 沸点：
  664.7±65.0 °C(Predicted)
• 密度：
  1.150±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥31mg/mL（60.11mM）

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  78.5
• 氢给体数：
  1
• 氢受体数：
  10

制备方法与用途

生物活性

UNC0321 是一种有效的选择性组蛋白甲基转移酶 G9a 抑制剂，其 Ki 值为 63 pM，IC50 值为 6-9 nM。此外，UNC0321 还能抑制 GLP，IC50 值为 15-23 nM。值得注意的是，UNC0321 对 SET7/9、SET8/PreSET7、PRMT3 和 JMJD2E 没有活性。

靶点

靶点	Ki/IC50 值
G9a	63 pM (Ki)
	6-9 nM (IC50)
GLP	15-23 nM (IC50)

体外研究

在 G9a ECSD 和 CLOT 实验中，UNC0321（化合物 29）的 IC50 值分别为 9 nM 和 6 nM。在 GLP ECSD 和 CLOT 实验中，其 IC50 值分别为 15 nM 和 23 nM。此外，在 MDA-MB-231 细胞中，UNC0321（化合物 3）能将 H3K9me2 水平降低至 IC50 的 11 μM。

反应信息

• 作为产物：
  描述：

  N,N-二甲基氨乙基乙二醇 、 6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-(1-methylpiperidin-4-ylamino)quinazolin-7-ol 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 生成 7-[2-[2-(二甲基氨基)乙氧基]乙氧基]-2-(六氢-4-甲基-1H-1,4-二氮杂卓-1-基)-6-甲氧基-N-(1-甲基-4-哌啶基)-4-喹唑啉胺
  参考文献：
  名称：

  Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.

  摘要：

  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.

  DOI：

  10.1021/jm100478y

文献信息

• EPIGENETIC REGULATORS OF FRATAXIN
  申请人：RANA THERAPEUTICS, INC.

  公开号：US20160201063A1

  公开（公告）日：2016-07-14

  Provided herein are methods for increasing Frataxin (FXN) expression that involve targeting or expressing regulatory factors that modulate the epigenetic state of FXN genes. Also provided herein are methods for increasing FXN expression using inhibitors of a negative epigenetic regulator of FXN. Compositions and methods for treating Friedrich's ataxia are also provided.
• TREATMENT OF DIABETES AND ASSOCIATED METABOLIC CONDITIONS WITH EPIGENETIC MODULATORS
  申请人：Temple Otorongo LLC

  公开号：US20190374525A1

  公开（公告）日：2019-12-12

  The present invention describes small molecules that have the activity of directly enhancing insulin sensitivity through epigenetic regulation. These small molecules, therefore, provide a new path for the treatment of type 2 diabetes and insulin resistance in type 1 diabetes or prediabetes and also can be used to treat obesity and chronic liver disease. Methods and compositions including these small molecules or for their administration are described. The methods and compositions can include additional anti-diabetic agents.
• [EN] EPIGENETIC REGULATORS OF FRATAXIN<br/>[FR] RÉGULATEURS ÉPIGÉNÉTIQUES DE LA FRATAXINE
  申请人：RANA THERAPEUTICS INC

  公开号：WO2015023938A1

  公开（公告）日：2015-02-19

  Provided herein are methods for increasing Frataxin (FXN) expression that involve targeting or expressing regulatory factors that modulate the epigenetic state of FXN genes. Also provided herein are methods for increasing FXN expression using inhibitors of a negative epigenetic regulator of FXN. Compositions and methods for treating Friedrich' s ataxia are also provided.
• [EN] TREATMENT OF DIABETES AND ASSOCIATED METABOLIC CONDITIONS WITH EPIGENETIC MODULATORS<br/>[FR] TRAITEMENT DU DIABÈTE ET D'ÉTATS MÉTABOLIQUES ASSOCIÉS AU MOYEN DE MODULATEURS ÉPIGÉNÉTIQUES
  申请人：TEMPLE OTORONGO LLC

  公开号：WO2018148206A1

  公开（公告）日：2018-08-16

  The present invention describes small molecules that have the activity of directly enhancing insulin sensitivity through epigenetic regulation. These small molecules, therefore, provide a new path for the treatment of type 2 diabetes and insulin resistance in type 1 diabetes or prediabetes and also can be used to treat obesity and chronic liver disease. Methods and compositions including these small molecules or for their administration are described. The methods and compositions can include additional anti-diabetic agents.
• [EN] INHIBITORS OF LYSINE METHYLTRANSFERASE FOR TREATMENT OF PAIN<br/>[FR] INHIBITEURS DE LYSINE MÉTHYLTRANSFÉRASE DESTINÉS AU TRAITEMENT DE LA DOULEUR
  申请人：UMC UTRECHT HOLDING BV

  公开号：WO2018190713A1

  公开（公告）日：2018-10-18

  The invention relates to a specific inhibitor of FAM173B mitochondrial lysine methyltransferase for use as a medicament, more specifically for use in a method of treatment of chronic pain. The invention further relates to a pharmaceutical composition comprising a specific inhibitor of FAM173B mitochondrial lysine methyltransferase, to the use of this composition in a method of treatment of chronic pain, to methods of typing an individual suffering from pain, and to methods of treating an individual suffering from pain.