3-(4-methylphenylsulfonamido)-N-(pyridin-4-yl)isonicotinamide trifluoroacetate

• 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: 3-(4-methylphenylsulfonamido)-N-(pyridin-4-yl)isonicotinamide trifluoroacetate
• 英文别名: 3-[(4-methylphenyl)sulfonylamino]-N-pyridin-4-ylpyridine-4-carboxamide;2,2,2-trifluoroacetic acid
• 化学式: (x)C₂HF₃O₂*C₁₈H₁₆N₄O₃S
• 分子量: 482.4
• InChiKey: HUYIKTMRSHCIJU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.47
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  147
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-氨基吡啶 、 3-(4-methylphenylsulfonamido)isonicotinic acid 、 三氟乙酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 、 水 、 乙腈 为溶剂， 反应 12.0h， 以62%的产率得到3-(4-methylphenylsulfonamido)-N-(pyridin-4-yl)isonicotinamide trifluoroacetate
  参考文献：
  名称：

  Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models

  摘要：

  Deubiquitinases are important components of the protein degradation regulatory network. We report the discovery of ML364, a small molecule inhibitor of the deubiquitinase USP2 and its use to interrogate the biology of USP2 and its putative substrate cyclin DL ML364 has an IC50 of 1.1 mu M in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate. Direct binding of ML364 to USP2 was demonstrated using microscale thermophoresis. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest as shown in Western blottings and flow cytometry assays utilizing both Mino and HCT116 cancer cell lines. ML364, and not the inactive analog 2, was antiproliferative in cancer cell lines. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth.

  DOI：

  10.1074/jbc.m116.738567

文献信息

• Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models
  作者：Mindy I. Davis、Rajan Pragani、Jennifer T. Fox、Min Shen、Kalindi Parmar、Emily F. Gaudiano、Li Liu、Cordelle Tanega、Lauren McGee、Matthew D. Hall、Crystal McKnight、Paul Shinn、Henrike Nelson、Debasish Chattopadhyay、Alan D. D'Andrea、Douglas S. Auld、Larry J. DeLucas、Zhuyin Li、Matthew B. Boxer、Anton Simeonov

  DOI：10.1074/jbc.m116.738567

  日期：2016.11

  Deubiquitinases are important components of the protein degradation regulatory network. We report the discovery of ML364, a small molecule inhibitor of the deubiquitinase USP2 and its use to interrogate the biology of USP2 and its putative substrate cyclin DL ML364 has an IC50 of 1.1 mu M in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate. Direct binding of ML364 to USP2 was demonstrated using microscale thermophoresis. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest as shown in Western blottings and flow cytometry assays utilizing both Mino and HCT116 cancer cell lines. ML364, and not the inactive analog 2, was antiproliferative in cancer cell lines. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth.