N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)quinazolin-6-yl)ethyl)-3-hydroxy-3-methylbutanamide

• 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: N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)quinazolin-6-yl)ethyl)-3-hydroxy-3-methylbutanamide
• 英文别名: N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]quinazolin-6-yl]ethyl]-3-hydroxy-3-methylbutanamide
• 化学式: C₂₈H₂₆ClF₃N₄O₃
• 分子量: 558.988
• InChiKey: PDXFYKHCQHPMFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  96.4
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-氨基-5-氯苯腈 在 四(三苯基膦)钯 、 (1,1'-双(二苯基膦)二茂铁)二氯化镍 、 1,3-双(二苯基膦)丙烷 、 1-羟基苯并三唑 、 caesium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 76.0h， 生成 N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)quinazolin-6-yl)ethyl)-3-hydroxy-3-methylbutanamide
  参考文献：
  名称：

  Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent

  摘要：

  The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase-ligand interaction space in the PDB.

  DOI：

  10.2147/dddt.s85357

文献信息

• Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent
  作者：Li Cai、Wei Liu、Jin-Feng Ning、Wei-Qing Meng、Jing Hu、Yan-Bin Zhao、Chao Liu

  DOI：10.2147/dddt.s85357

  日期：——

  The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase-ligand interaction space in the PDB.