(2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-4-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-[[2-(1H-indol-3-yl)-2-oxoacetyl]amino]butanediamide | 1252801-31-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-4-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-[[2-(1H-indol-3-yl)-2-oxoacetyl]amino]butanediamide
• CAS: 1252801-31-2
• 化学式: C₃₄H₃₇ClN₆O₅
• 分子量: 645.158
• InChiKey: LJQBIIJYQRCLSH-NSOVKSMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  46
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  162
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  邻氯苯甲胺 在 N-甲基吗啉 、 盐酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.0h， 生成 (2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-4-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-[[2-(1H-indol-3-yl)-2-oxoacetyl]amino]butanediamide
  参考文献：
  名称：

  Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

  摘要：

  通过共价抑制剂抑制蛋白酶体是一种临床验证过的抗癌疗法。我们在此报告，含有P3新戊酰胺残基的二肽能够有效地、可逆地、非共价地选择性抑制20S蛋白酶体在体外和细胞内的胰蛋白酶活性。化合物20与酵母20S的X射线结构揭示了新戊基团在20S β5亚基S3结合口袋中的疏水键结合作用的重要性。在多项检测中，四种化合物的效力与硼酸抑制剂相当。

  DOI：

  10.1039/c2md20060k

文献信息

• Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S β5-subunit
  作者：Christopher Blackburn、Kenneth M. Gigstad、Paul Hales、Khristofer Garcia、Matthew Jones、Frank J. Bruzzese、Cynthia Barrett、Jane X. Liu、Teresa A. Soucy、Darshan S. Sappal、Nancy Bump、Edward J. Olhava、Paul Fleming、Lawrence R. Dick、Christopher Tsu、Michael D. Sintchak、Jonathan L. Blank

  DOI：10.1042/bj20100383

  日期：2010.9.15

  The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome used on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin–proteasome system in cells. We show that these compounds are entirely selective for the β5 (chymotrypsin-like) site over the β1 (caspase-like) and β2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S β5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin–luciferase reporter, activation of NFκB (nuclear factor κB) in response to TNF-α (tumour necrosis factor-α) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the β5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the β5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.

  哺乳动物 26S 蛋白酶体是一种 2500 kDa 的多催化复合体，参与细胞内蛋白质的降解。我们描述了一系列新型蛋白酶体非共价二肽抑制剂的合成和特性，这些抑制剂使用了一种带帽三肽，是通过高通量筛选细胞中泛素-蛋白酶体系统抑制剂的约 35 万个化合物库首次发现的。我们的研究表明，这些化合物对蛋白酶体 20S 核心颗粒的 β5（类糜蛋白酶）位点具有完全的选择性，而对 β1（类 Caspase）和 β2（类胰蛋白酶）位点则没有选择性。以配体 20S 核心颗粒的 X 射线晶体学为指导，对化合物进行了优化，确认了它们的非共价结合模式，并为它们增强体外和细胞效力提供了结构基础。我们证明，这些化合物在体外对人类 20S β5 位点的 IC50 值很低，而且在细胞中对该位点的药理抑制足以有效抑制四泛素-荧光素酶报告物的降解、NFκB（核因子κB）对 TNF-α（肿瘤坏死因子-α）的活化以及癌细胞的增殖。最后，我们发现了在体外和 B 细胞淋巴瘤中对组成型表达蛋白酶体和免疫蛋白酶体的 β5 位点具有不同选择性的封端二肽。总之，这些研究描述了一系列新的非共价蛋白酶体抑制剂的合成、活性和结合模式，它们具有前所未有的效力和对β5位点的选择性，并能在体外和细胞内区分组成型蛋白酶体和免疫蛋白酶体。
• Protein degradation inducing tag and usage thereof
  申请人：Tokyo University of Science Foundation

  公开号：US10976306B2

  公开（公告）日：2021-04-13

  Provided are: a protein degradation inducing tag which is a molecule that has affinity with proteases and does not inhibit degradation of a protein by proteases; a protein degradation inducing molecule that is a conjugate of at least one protein degradation inducing tag and at least one protein binding molecule that binds to a protein; and a usage of those.

  提供了：一种蛋白质降解诱导标签，它是一种与蛋白酶具有亲和力的分子，不会抑制蛋白酶对蛋白质的降解；一种蛋白质降解诱导分子，它是至少一种蛋白质降解诱导标签和至少一种与蛋白质结合的蛋白质结合分子的共轭物；以及它们的用法。
• P53 degradation inducing molecule and pharmaceutical composition
  申请人：Tokyo University of Science Foundation

  公开号：US11007269B2

  公开（公告）日：2021-05-18

  A p53 degradation inducing molecule which can induce degradation of p53 proteins or p53 composites, and a pharmaceutical composition containing said p53 degradation inducing molecule are provided. This p53 degradation inducing molecule is a conjugate of a p53 affinity molecule which has affinity for p53 proteins or p53 composites, and a proteolysis induction tag which has affinity for protease and which does not inhibit proteolysis of proteins by protease.

  本发明提供了一种可诱导 p53 蛋白或 p53 复合物降解的 p53 降解诱导分子，以及一种含有所述 p53 降解诱导分子的药物组合物。这种 p53 降解诱导分子是对 p53 蛋白质或 p53 复合物具有亲和力的 p53 亲和分子与对蛋白酶具有亲和力且不抑制蛋白酶对蛋白质的蛋白水解的蛋白水解诱导标签的共轭物。
• Ras protein degradation inducing molecule and pharmaceutical composition
  申请人：Tokyo University of Science Foundation

  公开号：US11052154B2

  公开（公告）日：2021-07-06

  A Ras protein degradation inducing molecule that can induce degradation of Ras proteins, and a pharmaceutical composition that contains this Ras protein degradation inducing molecule are provided. The Ras protein degradation inducing molecule is a conjugate of a Ras protein affinity molecule which has affinity to Ras proteins, and a proteolysis-inducing tag which has affinity to protease and does not inhibit proteolysis of proteins by the protease.

  本发明提供了一种可诱导 Ras 蛋白降解的 Ras 蛋白降解诱导分子，以及一种含有这种 Ras 蛋白降解诱导分子的药物组合物。Ras 蛋白降解诱导分子是与 Ras 蛋白亲和的 Ras 蛋白亲和分子和与蛋白酶亲和的蛋白水解诱导标签的共轭物，蛋白水解诱导标签不抑制蛋白酶对蛋白质的蛋白水解。
• PROTEIN DEGRADATION INDUCING TAG AND USAGE THEREOF
  申请人：Tokyo University of Science Foundation

  公开号：US20180164289A1

  公开（公告）日：2018-06-14

  Provided are: a protein degradation inducing tag which is a molecule that has affinity with proteases and does not inhibit degradation of a protein by proteases; a protein degradation inducing molecule that is a conjugate of at least one protein degradation inducing tag and at least one protein binding molecule that binds to a protein; and a usage of those.