N-[1-(环己基甲基)-4-哌啶基]-2-[六氢-4-异丙基-1H-1,4-二氮杂卓-1-基]-6-甲氧基-7-[3-(1-哌啶基)丙氧基]-4-喹唑啉胺 | 1320288-19-4

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 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: N-[1-(环己基甲基)-4-哌啶基]-2-[六氢-4-异丙基-1H-1,4-二氮杂卓-1-基]-6-甲氧基-7-[3-(1-哌啶基)丙氧基]-4-喹唑啉胺
• 中文别名: G9A抑制剂(UNC0631)；化合物UNC0631
• 英文名称: N-(1-(cyclohexylmethyl)piperidin-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine
• 英文别名: UNC0631；N-[1-(cyclohexylmethyl)piperidin-4-yl]-6-methoxy-7-(3-piperidin-1-ylpropoxy)-2-(4-propan-2-yl-1,4-diazepan-1-yl)quinazolin-4-amine
• CAS: 1320288-19-4
• 化学式: C₃₇H₆₁N₇O₂
• 分子量: 635.937
• InChiKey: XFAXSWXKPQWHDW-UHFFFAOYSA-N

物化性质

• 沸点：
  763.4±70.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)
• 溶解度：
  不溶于水； ≥12.66 mg/mL，乙醇溶液，超声波；温和升温下 DMSO 中≥18.35 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  69.2
• 氢给体数：
  1
• 氢受体数：
  9

制备方法与用途

生物活性

UNC 0631 是一种有效的组蛋白甲基转移酶 G9a 抑制剂，IC50 值为 4 nM。它能有效降低 MDA-MB-231 细胞中 H3K9me2 的水平，IC50 为 25 nM。

靶点

| | G9a | 4 nM (IC₅₀) |

体外研究

UNC 0631（Compound 7）在多种细胞系中表现出高细胞活性和优异的功能效力与细胞毒性分离。它能有效降低 H3K9me2 的水平，并且具有较低的细胞毒性。具体来说，UNC 0631 在不同细胞系中的 IC50 值分别为 MDA-MB-231（25 nM）、MCF7（18 nM）、PC3（26 nM）、22RV1（24 nM）、HCT116 wt（51 nM）、HCT 116 p53^-/-（72 nM）和 IMR90 细胞系（46 nM）。

反应信息

• 作为产物：
  描述：

  苯甲酸,4-(3-氯丙氧基)-3-甲氧基-,甲基酯 在 ammonium acetate 、 水 、 硝酸 、 乙酸酐 、 四丁基碘化铵 、 铁粉 、 potassium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N,N-二乙基苯胺 、 sodium iodide 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 异丙醇 、 乙腈 为溶剂， 反应 10.25h， 生成 N-[1-(环己基甲基)-4-哌啶基]-2-[六氢-4-异丙基-1H-1,4-二氮杂卓-1-基]-6-甲氧基-7-[3-(1-哌啶基)丙氧基]-4-喹唑啉胺
  参考文献：
  名称：

  Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines

  摘要：

  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.

  DOI：

  10.1021/jm200903z

文献信息

• SUBSTITUTED 4-AMINOISOINDOLINE-1,3-DIONE COMPOUNDS AND SECOND ACTIVE AGENTS FOR COMBINED USE
  申请人：Celgene Corporation

  公开号：US20210113576A1

  公开（公告）日：2021-04-22

  Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with a second active agent for treating, preventing or managing hematological malignancies. The second active agent is one or more of an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, an Aurora kinase inhibitor, an EZH2 inhibitor, a BET inhibitor, a hypomethylating agent, a DOT1L inhibitor, a HAT inhibitor, a WDR5 inhibitor, a DNMT1 inhibitor, an LSD-1 inhibitor, a G9A inhibitor, a PRMT5 inhibitor, a BRD inhibitor, a SUV420H1/H2 inhibitor, a CARM1 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an MEK inhibitor, a PHF19 inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, a BIRC5 inhibitor, or a chemotherapy.

  本文提供了使用(S)-2-(2,6-二酮哌啶-3-基)-4-((2-氟-4-((3-吗啡基氮杂环丙烷-1-基)甲基)苯甲基)氨基)异吲哚啉-1,3-二酮或其对映体、对映体混合物、互变异构体、同位素拓扑异构体或其药学上可接受的盐，与第二种活性剂联合治疗、预防或管理血液恶性肿瘤的方法。第二种活性剂是HDAC抑制剂、BCL2抑制剂、BTK抑制剂、mTOR抑制剂、PI3K抑制剂、PKCβ抑制剂、SYK抑制剂、JAK2抑制剂、极化分裂素激酶抑制剂、EZH2抑制剂、BET抑制剂、去甲基化剂、DOT1L抑制剂、HAT抑制剂、WDR5抑制剂、DNMT1抑制剂、LSD-1抑制剂、G9A抑制剂、PRMT5抑制剂、BRD抑制剂、SUV420H1/H2抑制剂、CARM1抑制剂、PLK1抑制剂、NEK2抑制剂、MEK抑制剂、PHF19抑制剂、PIM抑制剂、IGF-1R抑制剂、XPO1抑制剂、BIRC5抑制剂或化疗药物之一。
• METHODS FOR TREATING A HEMATOLOGICAL CANCER AND THE USE OF COMPANION BIOMARKERS FOR 2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((2-FLUORO-4-((3-MORPHOLINOAZETIDIN-1-YL)METHYL)BENZYL)AMINO)ISOINDOLINE-1,3-DIONE
  申请人：CELGENE CORPORATION

  公开号：US20210116454A1

  公开（公告）日：2021-04-22

  A method of identifying a subject having a hematological cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the hematological cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2, or Compound 3.

  一种识别可能对治疗化合物有反应的血液肿瘤患者的方法，包括给患有血液肿瘤的受试者注射治疗化合物，从受试者获取样本，测定样本中生物标志物的水平，并在与生物标志物的参考水平相比，如果受试者样本中生物标志物的水平发生变化，则诊断受试者可能对治疗化合物有反应；其中，治疗化合物是化合物1、化合物2或化合物3。
• 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.
• [EN] METHODS FOR TREATING A HEMATOLOGICAL CANCER AND THE USE OF COMPANION BIOMARKERS FOR 2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((2-FLUORO-4-((3-MORPHOLINOAZETIDIN-1-YL)METHYL)BENZYL)AMINO)ISOINDOLINE-1,3-DIONE<br/>[FR] MÉTHODES DE TRAITEMENT D'UN CANCER HÉMATOLOGIQUE ET UTILISATION DE BIOMARQUEURS COMPAGNONS POUR 2-(2,6-DIOXOPIPÉRIDIN-3-YL)-4-((2-FLUORO-4-((3-MORPHOLINOAZÉTIDIN-1-YL)MÉTHYL)BENZYL)AMINO)ISOINDOLINE-1,3-DIONE
  申请人：CELGENE CORP

  公开号：WO2021080950A1

  公开（公告）日：2021-04-29

  A method of identifying a subject having a hematological cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the hematological cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2, or Compound 3.
• [EN] SUBSTITUTED 4-AMINOISOINDOLINE-1,3-DIONE COMPOUNDS AND SECOND ACTIVE AGENTS FOR COMBINED USE<br/>[FR] COMPOSÉS DE 4-AMINOISOINDOLINE -1,3-DIONE SUBSTITUÉS ET SECONDS AGENTS ACTIFS À USAGE COMBINÉ
  申请人：CELGENE CORP

  公开号：WO2021080955A1

  公开（公告）日：2021-04-29

  Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3- morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with a second active agent for treating, preventing or managing hematological malignancies. The second active agent is one or more of an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, an Aurora kinase inhibitor, an EZH2 inhibitor, a BET inhibitor, a hypomethylating agent, a DOT1L inhibitor, a HAT inhibitor, a WDR5 inhibitor, a DNMT1 inhibitor, an LSD-1 inhibitor, a G9A inhibitor, a PRMT5 inhibitor, a BRD inhibitor, a SUV420H1/H2 inhibitor, a CARM1 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an MEK inhibitor, a PHF19 inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, a BIRC5 inhibitor, or a chemotherapy.