1-methyl-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1H-indazole-3-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-methyl-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1H-indazole-3-carboxamide
• 英文别名: 1-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]indazole-3-carboxamide
• 化学式: C₂₀H₂₂N₆O₃
• 分子量: 394.433
• InChiKey: YSYGVXBESJSFEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氟-5-硝基苯胺 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 对二甲苯 为溶剂， 反应 5.0h， 生成 1-methyl-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1H-indazole-3-carboxamide
  参考文献：
  名称：

  Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)

  摘要：

  WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-S substituents. This allowed us to develop the first highly potent (K-disp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

  DOI：

  10.1021/acs.jmedchem.5b01630

文献信息

• Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)
  作者：Matthäus Getlik、David Smil、Carlos Zepeda-Velázquez、Yuri Bolshan、Gennady Poda、Hong Wu、Aiping Dong、Ekaterina Kuznetsova、Richard Marcellus、Guillermo Senisterra、Ludmila Dombrovski、Taraneh Hajian、Taira Kiyota、Matthieu Schapira、Cheryl H. Arrowsmith、Peter J. Brown、Masoud Vedadi、Rima Al-awar

  DOI：10.1021/acs.jmedchem.5b01630

  日期：2016.3.24

  WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-S substituents. This allowed us to develop the first highly potent (K-disp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.