RL40 | 1220448-92-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: RL40
• 英文别名: N-(4-(1H-pyrazol-3-ylamino)-2-phenylquinazolin-7-yl)acrylamide；N-[2-Phenyl-4-(1h-Pyrazol-3-Ylamino)quinazolin-7-Yl]prop-2-Enamide；N-[2-phenyl-4-(1H-pyrazol-5-ylamino)quinazolin-7-yl]prop-2-enamide
• CAS: 1220448-92-9
• 化学式: C₂₀H₁₆N₆O
• 分子量: 356.387
• InChiKey: DBXZXNJCPSGVAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  95.6
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-phenyl-N4-(1H-pyrazol-3-yl)quinazolin-4,7-diamine 、 丙烯酰氯 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以26%的产率得到RL40
  参考文献：
  名称：

  Fluorophore Labeling of the Glycine-Rich Loop as a Method of Identifying Inhibitors That Bind to Active and Inactive Kinase Conformations

  摘要：

  Targeting protein kinases with small organic molecules is a promising strategy to regulate unwanted kinase activity in both chemical biology and medicinal chemistry research. Traditionally, kinase inhibitors are identified in activity-based screening assays using enzymatically active kinase preparations to measure the perturbation of substrate phosphorylation, often resulting in the enrichment of classical ATP competitive (Type I) inhibitors. However, addressing enzymatically incompetent kinase conformations offers new opportunities for targeted therapies and is moving to the forefront of kinase inhibitor research. Here we report the development of a new FLiK (Fluorescent Labels in Kinases) binding assay to detect small molecules that induce changes in the conformation of the glycine-rich loop. Due to cross-talk between the glycine-rich loop and the activation loop in kinases, this alternative labeling approach can also detect ligands that stabilize inactive kinase conformations, including slow-binding Type II and Type Ill kinase inhibitors. Protein X-ray crystallography validated the assay results and identified a novel DFG-out binding mode for a quinazoline-based inhibitor in p38 alpha kinase. We also detected the high-affinity binding of a clinically relevant and specific VEGFR2 inhibitor, and we provide structural details of its binding mode in p38a, in which it stabilizes the DFG-out conformation. Last, we demonstrate the power of this new FLiK labeling strategy to detect the binding of Type I ligands that induce conformational changes in the glycine-rich loop as a means of gaining affinity for the target kinase. This approach may be a useful alternative to develop direct binding assays for kinases that do not adopt the DFG-out conformation while also avoiding the use of expensive kits, detection reagents, or radioactivity frequently employed with activity-based assays.

  DOI：

  10.1021/ja908083e