3-[5-[4-(2-羟基-2-甲基-1-氧丙基)-1-哌嗪基]-2-(三氟甲基)苯基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮 | 1260181-14-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 3-[5-[4-(2-羟基-2-甲基-1-氧丙基)-1-哌嗪基]-2-(三氟甲基)苯基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮
• 中文别名: 化合物TCS21311
• 英文名称: NIBR3049
• 英文别名: 3-[5-[4-(2-Hydroxy-2-methyl-1-oxopropyl)-1-piperazinyl]-2-(trifluoromethyl)phenyl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione；3-[5-[4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl]-2-(trifluoromethyl)phenyl]-4-(1H-indol-3-yl)pyrrole-2,5-dione
• CAS: 1260181-14-3
• 化学式: C₂₇H₂₅F₃N₄O₄
• 分子量: 526.515
• InChiKey: CLGRAWDGLMENOD-UHFFFAOYSA-N

物化性质

• 沸点：
  793.0±60.0 °C(Predicted)
• 密度：
  1.436±0.06 g/cm3(Predicted)
• 溶解度：
  <52.65mg/ml，溶于 DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  8

制备方法与用途

生物活性

TCS 21311 (NIBR3049) 是一种高效的高选择性 JAK3 抑制剂，其 IC50 值为 8 nM。它对 JAK1、JAK2 和 TYK2 的选择性分别是 JAK3 的 100 倍以上。此外，TCS 21311 (NIBR3049) 还能抑制 PKCα、PKCθ 和 GSK3β，其 IC50 值分别为 13 nM、68 nM 和 3 nM。

靶点

• JAK3：8 nM (IC50)
• JAK2：2.55 μM (IC50)
• JAK1：1.017 μM (IC50)
• PKCα：13 nM (IC50)
• PKCθ：68 nM (IC50)
• GSK-3β：3 nM (IC50)

体外研究

在酶促 JAK 活性测定中，TCS 21311 (NIBR3049) 的 IC50 值分别为 JAK1、JAK2 和 TYK2 的 1.017 μM、2.550 μM 和 8.055 μM。在细胞实验中，TCS 21311 (NIBR3049) 表现出适度的活性（IC50 = 689 nM，在 Jurkat 细胞中），这与其酶促 PKC 活性一致。

用途

TCS 21311 (NIBR3049) 是一种强效 JAK3 抑制剂，选择性高于 JAK1、JAK2 和 TYK2。它还能抑制 GSK-3β、PKCα 和 PKCθ。

反应信息

• 作为产物：
  描述：

  3-(5-fluoro-2-(trifluoromethyl)phenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione 在 4-二甲氨基吡啶 、 sodium methylate 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 为溶剂， 反应 3.5h， 生成 3-[5-[4-(2-羟基-2-甲基-1-氧丙基)-1-哌嗪基]-2-(三氟甲基)苯基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮
  参考文献：
  名称：

  Identification of a Potent Janus Kinase 3 Inhibitor with High Selectivity within the Janus Kinase Family

  摘要：

  We describe a synthetic approach toward the rapid modification of phenyl-indolyl maleimides and the discovery of potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family We provide a rationale for this unprecedented selectivity based on the X-ray crystal structure of an analogue of 1 bound to the ATP-binding site of Jak3 While equally potent compared to the Pfizer pan Jak inhibitor CP-690,550 (2) in an enzymatic Jak3 assay, compound 1 was found to be 20 fold less potent in cellular assays measuring cytokine-triggered signaling through cytokine receptors containing the common gamma chain (gamma C) Contrary to compound 1, compound 2 inhibited Jak1 in addition to Jak3 Permeability and cellular concentrations of compounds 1 and 2 were similar As Jak3 always cooperates with Jak 1 for signaling, we speculate that specific inhibition of Jak3 is not sufficient to efficiently block gamma C cytokine signal transduction required for strong immunosuppression

  DOI：

  10.1021/jm101157q

文献信息

• METHOD OF TREATMENT OF PARKINSONISM
  申请人：Fundacio Centre de Regulacio Genomica

  公开号：EP3231434A1

  公开（公告）日：2017-10-18

  The invention relates to a cell selected from the group consisting of a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), and a mesenchymal stem cell (MSC), or a cell population comprising any combination thereof, for use in the treatment of Parkinsonism in a subject, and to pharmaceutical compositions and kits for use in the treatment of Parkinsonism.

  本发明涉及一种选自造血干细胞（HSC）、造血祖细胞（HPC）和间充质干细胞（MSC）组成的组的细胞，或由其任意组合而成的细胞群，用于治疗受试者的帕金森病，还涉及用于治疗帕金森病的药物组合物和试剂盒。
• MEDIUM FOR CULTURING STEM CELLS, METHOD FOR CULTURING STEM CELLS, STEM CELL GROWTH PROMOTER, AND CELL COMPOSITION AND METHOD FOR PRODUCING SAME
  申请人：Kyowa Hakko Bio Co., Ltd.

  公开号：EP3511410A1

  公开（公告）日：2019-07-17

  An object of the present invention is to provide a technique for stably, inexpensively, and safely culturing stem cells having a differentiation ability while maintaining an undifferentiated state. The present invention relates to a medium for culturing stem cells, comprising at least one or more compounds selected from the group consisting of a ROCK inhibitor, a PKC inhibitor, a histone methyltransferase inhibitor, and a retinoic acid receptor agonist, and not containing a growth factor or having a low growth factor concentration; a method for culturing stem cells using the medium; a growth promoter for stem cell; as well as a cell composition containing stem cells or differentiated cells therefrom; and a method for producing the cell composition.

  本发明的目的是提供一种技术，稳定、廉价、安全地培养具有分化能力的干细胞，同时保持未分化状态。本发明涉及一种培养干细胞的培养基，该培养基包含至少一种或多种选自 ROCK 抑制剂、PKC 抑制剂、组蛋白甲基转移酶抑制剂和维甲酸受体激动剂的化合物，且不含生长因子或生长因子浓度较低；一种使用该培养基培养干细胞的方法；一种干细胞生长促进剂；以及一种含有干细胞或从中分化的细胞的细胞组合物；以及一种生产该细胞组合物的方法。
• Compositions and methods for epithelial stem cell expansion and culture
  申请人：The Brigham and Women's Hospital, Inc.

  公开号：US10041046B2

  公开（公告）日：2018-08-07

  Described are cell culture solutions and systems for epithelial stem cell and organoid cultures, formation of epithelial constructs and uses of the same in transplantation. A single layer of epithelial cells that actively self-renews and is organized into crypts and villi clothes the intestine. It has been recently shown that the renewal of intestinal epithelium is driven by Lgr5+ intestinal stem cells (ISC) that reside at the base of these crypts (Barker et al., 2007). Lgr5+ stem cells can be isolated and cultured in vitro to form organoids containing crypt-vcllus structures that recapitulates the native intestinal epithelium (Sato et al., 2009).

  描述了用于上皮干细胞和类器官培养的细胞培养液和系统、上皮构建体的形成及其在移植中的应用。上皮细胞是一种单层上皮细胞，能主动自我更新，并被组织成隐窝和绒毛，为肠道穿衣。最近的研究表明，肠上皮细胞的更新是由位于这些隐窝底部的Lgr5+肠干细胞（ISC）驱动的（Barker等人，2007年）。Lgr5+干细胞可被分离出来并在体外培养，形成含有隐窝-绒毛结构的器官组织，从而再现原生肠上皮（Sato等人，2009年）。
• Differentiation of hepatocyte-like cells from stem cells
  申请人：Agency for Science, Technology and Research

  公开号：US10323228B2

  公开（公告）日：2019-06-18

  Disclosed are methods of differentiating stem cells in order to obtain hepatocyte-like cells, the method comprising the steps of a) subjecting definitive endoderm to at least one epigenetic modulator to obtain hepatoblasts and b) subjecting the hepatoblasts to at least one stem cell differentiation pathway inhibitor to obtain hepatocyte-like cells; wherein steps a) and b) do not comprise the use of a growth factor. In one preferred embodiment, the epigenetic modulator may be sodium butyrate and/or DMSO and the stem cell differentiation pathway inhibitor may be SB431542 and/or DMSO. Also disclosed are hepatocyte-like cells obtained from the method and uses of these cells such as drug screening.

  本发明公开了分化干细胞以获得肝细胞样细胞的方法，该方法包括以下步骤：a)将确定的内胚层置于至少一种表观遗传调节剂中以获得肝母细胞；b)将肝母细胞置于至少一种干细胞分化途径抑制剂中以获得肝细胞样细胞；其中步骤a)和b)不包括使用生长因子。在一个优选的实施方案中，表观遗传调节剂可以是丁酸钠和/或二甲基亚砜，干细胞分化途径抑制剂可以是SB431542和/或二甲基亚砜。还公开了从该方法中获得的肝细胞样细胞以及这些细胞的用途，如药物筛选。
• Derivation of hepatic stem cells and mature liver cell types and uses thereof
  申请人：AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH

  公开号：US10683484B2

  公开（公告）日：2020-06-16

  This application describes liver stem cells (LSC), and differentiated hepatocytes, cholangiocytes, and 3D cellular structures derived therefrom. Methods for producing LSC and mature, differentiated hepatocytes and cholangiocytes in culture are provided. Also provided are cell culture systems and cell culture media for producing a homogenous population of liver stem cells that remain in an undifferentiated state over multiple passages in culture. The LSC and methods are useful for producing homogenous populations of hepatocytes and cholangiocytes for downstream applications. The LSC can be transplanted into subjects to treat liver diseases.

  本申请介绍了肝干细胞（LSC）、分化的肝细胞、胆管细胞以及由此衍生的三维细胞结构。本申请提供了在培养过程中产生 LSC 以及成熟、分化的肝细胞和胆管细胞的方法。此外，还提供了细胞培养系统和细胞培养基，用于产生在培养过程中多次传代保持未分化状态的同源肝干细胞群。这种肝干细胞和方法可用于生产下游应用所需的同源肝细胞和胆管细胞。肝干细胞可移植到受试者体内治疗肝脏疾病。