methyl (E)-4-(1-cyclopentyl-5-methoxy-2-methyl-1H-indole-3-carboxamido)but-2-enoate | 2307694-90-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl (E)-4-(1-cyclopentyl-5-methoxy-2-methyl-1H-indole-3-carboxamido)but-2-enoate
• 英文别名: 4-[(1-Cyclopentyl-2-methyl-5-methoxy-1H-indole-3-yl)carbonylamino]-2-butenoic acid methyl ester；methyl (E)-4-[(1-cyclopentyl-5-methoxy-2-methylindole-3-carbonyl)amino]but-2-enoate
• CAS: 2307694-90-0
• 化学式: C₂₁H₂₆N₂O₄
• 分子量: 370.448
• InChiKey: ONZCVJIBENGLKN-RMKNXTFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  69.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  methyl (E)-4-((tert-butoxycarbonyl)amino)but-2-enoate 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 methyl (E)-4-(1-cyclopentyl-5-methoxy-2-methyl-1H-indole-3-carboxamido)but-2-enoate
  参考文献：
  名称：

  A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism

  摘要：

  E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.

  DOI：

  10.1021/jacs.5b06839

文献信息

• Screening methods for the binding affinity of chemical entities to biological molecules and NEDD4-1 inhibitors identified by the screening methods
  申请人：Northwestern University

  公开号：US10273208B2

  公开（公告）日：2019-04-30

  Disclosed are methods for preparing and screening for an inhibitor of the activity of a biological molecule having a catalytic or non-catalytic cysteine residue. The methods including preparing a library of candidate inhibitor molecules by conjugating an electrophile to a plurality of drug molecules where the library of candidate inhibitor molecules thus formed react with cysteine residues. The library of candidate inhibitor molecules then may be reacted with the biological molecule to identify those inhibitor molecule that react with the catalytic or non-catalytic cysteine residue of the biological molecule in order to identify an inhibitor of the biological molecule.

  本发明公开了制备和筛选具有催化或非催化半胱氨酸残基的生物分子活性抑制剂的方法。这些方法包括制备候选抑制剂分子库，方法是将亲电子体与多个药物分子共轭，由此形成的候选抑制剂分子库与半胱氨酸残基发生反应。然后可将候选抑制剂分子库与生物分子反应，以确定那些与生物分子的催化或非催化半胱氨酸残基反应的抑制剂分子，从而确定生物分子的抑制剂。
• SCREENING METHODS FOR THE BINDING AFFINITY OF CHEMICAL ENTITIES TO BIOLOGICAL MOLECULES AND NEDD4-1 INHIBITORS IDENTIFIED BY THE SCREENING METHODS
  申请人：NORTHWESTERN UNIVERSITY

  公开号：US20160016893A1

  公开（公告）日：2016-01-21

  Disclosed are methods for screening for the binding affinity of chemical entities to other bioactive molecules. The screened chemical entities may be utilized in pharmaceutical composition or therapeutic methods for treating disease or disorders associated with the bioactive molecules including NEDD4-1.
• US9586890B2
  申请人：——

  公开号：US9586890B2

  公开（公告）日：2017-03-07