(((6-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)bis(phosphonic acid)

• 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: (((6-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)bis(phosphonic acid)
• 英文别名: US11279719, Example C-11；[[[6-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid
• 化学式: C₂₀H₁₈N₄O₇P₂S
• 分子量: 520.399
• InChiKey: TULSVKIMJXAWJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  210
• 氢给体数：
  6
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  tetraethyl (((6-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)bis(phosphonate) 在 三甲基溴硅烷 、 甲醇 作用下， 以 二氯甲烷 为溶剂， 生成 (((6-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)bis(phosphonic acid)
  参考文献：
  名称：

  Unraveling the Prenylation–Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors

  摘要：

  Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo down regulation of Rap 1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.

  DOI：

  10.1021/acs.jmedchem.8b00886

文献信息

• Unraveling the Prenylation–Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors
  作者：Cyrus M. Lacbay、Daniel D. Waller、Jaeok Park、Mònica Gómez Palou、Félix Vincent、Xian Fang Huang、Viviane Ta、Albert M. Berghuis、Michael Sebag、Youla S. Tsantrizos

  DOI：10.1021/acs.jmedchem.8b00886

  日期：2018.8.9

  Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo down regulation of Rap 1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.