(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-N-[(2S)-1-[[2-[[2-[3-[[4-(1H-indazol-3-yl)benzoyl]amino]propylamino]-2-oxoethyl]amino]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]butanediamide | 1032262-57-9

• 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)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-N-[(2S)-1-[[2-[[2-[3-[[4-(1H-indazol-3-yl)benzoyl]amino]propylamino]-2-oxoethyl]amino]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]butanediamide
• CAS: 1032262-57-9
• 化学式: C₃₉H₅₄N₁₀O₈
• 分子量: 790.92
• InChiKey: SQSOKJARZNAPEA-CHQNGUEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  57
• 可旋转键数：
  22
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  276
• 氢给体数：
  9
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  N-(3-氨基丙基)-4-(1H-吲唑-3-基)苯甲酰胺 、 Ac-LNLGG-OH 在 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以61%的产率得到(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-N-[(2S)-1-[[2-[[2-[3-[[4-(1H-indazol-3-yl)benzoyl]amino]propylamino]-2-oxoethyl]amino]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]butanediamide
  参考文献：
  名称：

  Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases

  摘要：

  We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.

  DOI：

  10.1021/jm800068w

文献信息

• [EN] BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES<br/>[FR] MODULATEURS DES LIAISONS BIDENTÉES DES KINASES LRRK2 ET JNK
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2014200682A1

  公开（公告）日：2014-12-18

  Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (Ml), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families.

  JNK和LRRK2都与帕金森病（PD）、心肌梗死（MI）和其他医学疾病相关联。在这里，我们报告了一种相对选择性和有效的激酶抑制剂（例如，化合物6和10），它们结合了JNK和LRRK2（双重抑制剂）。采用一种双齿结合策略，同时利用ATP铰链结合和ATP口袋外的独特蛋白表面位点，用于设计和识别这种抑制剂。化合物6是一种强效的JNK3和适度的LRRK2双重抑制剂，酶IC50值分别为12 nM和99 nM（LRRK2-G2019S）。6还表现出良好的细胞效力，在SHSY5Y细胞中抑制了LRRK2：G2019S诱导的线粒体功能障碍，并被证明对来自代表性激酶家族的116种激酶面板具有相当的选择性。
• BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US20160185818A1

  公开（公告）日：2016-06-30

  Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (MI), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families.

  JNK和LRRK2都与帕金森病（PD）、心肌梗死（MI）和其他医学疾病有关。在这里，我们报告了一种相对选择性和有效的激酶抑制剂（例如化合物6和10），它们结合了JNK和LRRK2（双重抑制剂）。采用一种双齿配体结合策略，同时利用ATP铰链结合和ATP口袋外的独特蛋白表面位点，设计和鉴定了这种抑制剂。化合物6是一种强效的JNK3和适度的LRRK2双重抑制剂，其酶IC50值分别为12 nM和99 nM（LRRK2-G2019S）。6还表现出良好的细胞效力，在SHSY5Y细胞中抑制了LRRK2：G2019S诱导的线粒体功能障碍，并被证明在代表性激酶家族的116个激酶面板中相对选择性较好。
• US9850276B2
  申请人：——

  公开号：US9850276B2

  公开（公告）日：2017-12-26
• Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases
  作者：Jesus Vazquez、Surya K. De、Li-Hsing Chen、Megan Riel-Mehan、Aras Emdadi、Jason Cellitti、John L. Stebbins、Michele F. Rega、Maurizio Pellecchia

  DOI：10.1021/jm800068w

  日期：2008.6.1

  We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.