(1-(3,4-difluorobenzyl)-2-oxo-N-{1(R)-2-[(2-oxo2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,2-dihydropyridine-3-carboxamide) | 1001409-50-2

• 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 - 苯并咪唑类
• 英文名称: (1-(3,4-difluorobenzyl)-2-oxo-N-{1(R)-2-[(2-oxo2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,2-dihydropyridine-3-carboxamide)
• 英文别名: KIN001-244；MP7；PDK1 inhibitor；1-[(3,4-difluorophenyl)methyl]-2-oxo-N-[(1R)-2-[(2-oxo-1,3-dihydrobenzimidazol-5-yl)oxy]-1-phenylethyl]pyridine-3-carboxamide
• CAS: 1001409-50-2
• 化学式: C₂₈H₂₂F₂N₄O₄
• 分子量: 516.504
• InChiKey: GCWCGSPBENFEPE-VWLOTQADSA-N

物化性质

• 沸点：
  724.4±60.0 °C(Predicted)
• 密度：
  1.398
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  99.8
• 氢给体数：
  3
• 氢受体数：
  6

制备方法与用途

生物活性

MP7 (PDK1抑制剂) 是一种磷酸肌醇依赖性激酶-1 (PDK1) 抑制剂。

靶点

PDK1

体外研究

细胞计数结果显示，乌87MG衍生的胶质瘤干细胞（GSCs）在阿利西替滨和微小程度上被MP7处理后，活细胞数量均有所减少。当这两种化合物联合使用时，对GSC存活率的影响更为显著。在乌87MG细胞中观察到，高浓度（即1.5 μM 阿利西替滨和2.5 μM MP7）处理后，死亡细胞的数量明显增加。经过72小时的治疗，仅MP7处理并未显示出对多形性胶质母细胞瘤（GBM）增殖的显著抑制作用。在多种癌细胞系中，MP7 对单层细胞生长的影响也十分有限，在微摩尔范围内IC50值较低。

反应信息

• 作为产物：
  描述：

  1-(3,4-二氟苄基)-2-氧代-1,2-二氢吡啶-3-羧酸 在 盐酸 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 锌 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 38.0h， 生成 (1-(3,4-difluorobenzyl)-2-oxo-N-{1(R)-2-[(2-oxo2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,2-dihydropyridine-3-carboxamide)
  参考文献：
  名称：

  Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

  摘要：

  We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.03.032

文献信息

• [EN] 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS DUAL INHIBITORS OF PDK1/AURA<br/>[FR] COMPOSÉS DE 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE ET LEUR UTILISATION À TITRE D'INHIBITEURS DOUBLES DE PDK1/AURA
  申请人：INTERNATIONAL SOC FOR DRUG DEVELOPMENT S R L

  公开号：WO2017211946A1

  公开（公告）日：2017-12-14

  The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) in the treatment of pathologies which require a dual inhibitor of PDK1/AurA enzymes such as for instance tumours, particularly glioblastoma.

  本发明涉及一种式（I）的2-氧代-1,2-二氢吡啶-3-羧酰胺化合物在需要PDK1/AurA酶的双重抑制剂治疗病理学中的应用，例如肿瘤，特别是胶质母细胞瘤。
• PYRIDINONYL PDK1 INHIBITORS
  申请人：Lind Kenneth Egnard

  公开号：US20100144730A1

  公开（公告）日：2010-06-10

  The present invention provides pyridinonyl PDK1 inhibitors and methods of treating cancer using the same.

  本发明提供了吡啶基PDK1抑制剂及其使用方法，用于治疗癌症。
• 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS DUAL INHIBITORS OF PDK1/AURA
  申请人：International Society for Drug Development S.r.l.

  公开号：EP3468556A1

  公开（公告）日：2019-04-17
• USES OF KINASE INHIBITORS FOR INDUCING AND MAINTAINING PLURIPOTENCY
  申请人：Whitehead Institute for Biomedical Research

  公开号：US20170114323A1

  公开（公告）日：2017-04-27

  The present disclosure provides compounds of any one of Formulae (A) to (L). The present disclosure also provides compositions, uses, and methods that include or involve a compound described herein, a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, or a combination thereof. The compounds, compositions, uses, and methods are useful in changing the pluripotency state of a vertebrate cell to a more naive state.
• MULTI-STAGE PERSONALIZED LONGEVITY THERAPEUTICS
  申请人：Insilico Medicine, Inc.

  公开号：US20190030078A1

  公开（公告）日：2019-01-31

  A method of treating senescence in a subject can include applying a senoremediation drug treatment protocol to the subject in order to rescue one or more first cells in the subject, wherein the senoremediation drug treatment protocol is derived from a computational transcriptome analysis of the tissue or organ of the subject. The method can include applying a senolytic drug treatment protocol to the subject in order to remove one or more second cells in the subject. The method can include introducing stem cells into a tissue and/or organ of the subject in order to rejuvenate one or more tissue cells in the tissue and/or one or more organ cells in the organ. The method can include carrying out a reinforcement step that includes one or more actions that prevent further senescence or degradation of the tissue or organ.