N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-{2-[2-(2-{[3-methoxy-4-({4-[(3-oxo-2,3-dihydro-1Hinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]-formamido}ethoxy)ethoxy]ethoxy}propanamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-{2-[2-(2-{[3-methoxy-4-({4-[(3-oxo-2,3-dihydro-1Hinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]-formamido}ethoxy)ethoxy]ethoxy}propanamide
• 英文别名: BI-3663；N-[2-[2-[2-[3-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethyl]-3-methoxy-4-[[4-[(3-oxo-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide；N-[2-[2-[2-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethyl]-3-methoxy-4-[[4-[(3-oxo-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide
• 化学式: C₄₄H₄₂F₃N₇O₁₂
• 分子量: 917.852
• InChiKey: ADTXLFJKQHYGPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  66
• 可旋转键数：
  20
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  243
• 氢给体数：
  4
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  泊马度胺 在 吡啶 、 palladium 10% on activated carbon 、 氢气 、 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~80.0 ℃ 、600.01 kPa 条件下， 反应 6.08h， 生成 N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-{2-[2-(2-{[3-methoxy-4-({4-[(3-oxo-2,3-dihydro-1Hinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]-formamido}ethoxy)ethoxy]ethoxy}propanamide
  参考文献：
  名称：

  Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

  摘要：

  Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.

  DOI：

  10.1021/acs.jmedchem.8b01826

文献信息

• Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions
  作者：Johannes Popow、Heribert Arnhof、Gerd Bader、Helmut Berger、Alessio Ciulli、David Covini、Christian Dank、Teresa Gmaschitz、Peter Greb、Jale Karolyi-Özguer、Manfred Koegl、Darryl B. McConnell、Mark Pearson、Maria Rieger、Joerg Rinnenthal、Vanessa Roessler、Andreas Schrenk、Markus Spina、Steffen Steurer、Nicole Trainor、Elisabeth Traxler、Corinna Wieshofer、Andreas Zoephel、Peter Ettmayer

  DOI：10.1021/acs.jmedchem.8b01826

  日期：2019.3.14

  Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.