N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine
• 英文别名: N-(5-Methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine (15a)；6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine
• 化学式: C₁₉H₂₂N₈O₃
• 分子量: 410.435
• InChiKey: GYXIFIORIDAIKZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine 在 palladium on activated charcoal 、 甲酸铵 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成
  参考文献：
  名称：

  Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

  摘要：

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

  DOI：

  10.1021/acs.jmedchem.5b01082
• 作为产物：
  描述：

  4,6-dichloro-2-(4-nitrophenoxy)pyrimidine 在 N,N-二异丙基乙胺 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine
  参考文献：
  名称：

  Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

  摘要：

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

  DOI：

  10.1021/acs.jmedchem.5b01082

文献信息

• Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach
  作者：Julian Engel、André Richters、Matthäus Getlik、Stefano Tomassi、Marina Keul、Martin Termathe、Jonas Lategahn、Christian Becker、Svenja Mayer-Wrangowski、Christian Grütter、Niklas Uhlenbrock、Jasmin Krüll、Niklas Schaumann、Simone Eppmann、Patrick Kibies、Franziska Hoffgaard、Jochen Heil、Sascha Menninger、Sandra Ortiz-Cuaran、Johannes M. Heuckmann、Verena Tinnefeld、René P. Zahedi、Martin L. Sos、Carsten Schultz-Fademrecht、Roman K. Thomas、Stefan M. Kast、Daniel Rauh

  DOI：10.1021/acs.jmedchem.5b01082

  日期：2015.9.10

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.