tert-butyl 2-(4-chlorophenoxy)-2-methylpropanoate | 124188-31-4

• 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: tert-butyl 2-(4-chlorophenoxy)-2-methylpropanoate
• CAS: 124188-31-4
• 化学式: C₁₄H₁₉ClO₃
• mdl: MFCD23391237
• 分子量: 270.756
• InChiKey: UTJLZSKUCKGULB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  哌啶 、 tert-butyl 2-(4-chlorophenoxy)-2-methylpropanoate 在 三氟乙酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 2-(4-chlorophenoxy)-2-methyl-1-(piperidin-1-yl)propan-1-one
  参考文献：
  名称：

  Site-Directed Fragment-Based Screening for the Discovery of Protein–Protein Interaction Stabilizers

  摘要：

  Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3 sigma and a peptide derived from Estrogen Receptor alpha (ER alpha), an important breast cancer target that is negatively regulated by 14-3-3 sigma. We identify orthosteric stabilizers that increase 14-3-3/ER alpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ER alpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.

  DOI：

  10.1021/jacs.8b11658
• 作为产物：
  描述：

  2-溴代异丁酸叔丁酯 、 对氯苯酚 在 magnesium sulfate 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 2-(4-chlorophenoxy)-2-methylpropanoate
  参考文献：
  名称：

  Site-Directed Fragment-Based Screening for the Discovery of Protein–Protein Interaction Stabilizers

  摘要：

  Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3 sigma and a peptide derived from Estrogen Receptor alpha (ER alpha), an important breast cancer target that is negatively regulated by 14-3-3 sigma. We identify orthosteric stabilizers that increase 14-3-3/ER alpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ER alpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.

  DOI：

  10.1021/jacs.8b11658

文献信息

• [EN] PROTEIN-PROTEIN INTERACTION STABILIZERS<br/>[FR] STABILISANTS D'INTERACTIONS PROTÉINE-PROTÉINE
  申请人：UNIV CALIFORNIA

  公开号：WO2021203016A3

  公开（公告）日：2021-11-04
• Clewley, Robin G.; Fischer, Alfred; Henderson, George N., Canadian Journal of Chemistry, 1989, vol. 67, p. 1472 - 1479
  作者：Clewley, Robin G.、Fischer, Alfred、Henderson, George N.

  DOI：——

  日期：——
• CLEWLEY, ROBIN G.;FISCHER, ALFRED;HENDERSON, GEORGE N., CAN. J. CHEM., 67,(1989) N, C. 1472-1479
  作者：CLEWLEY, ROBIN G.、FISCHER, ALFRED、HENDERSON, GEORGE N.

  DOI：——

  日期：——
• Site-Directed Fragment-Based Screening for the Discovery of Protein–Protein Interaction Stabilizers
  作者：Eline Sijbesma、Kenneth K. Hallenbeck、Seppe Leysen、Pim J. de Vink、Lukasz Skóra、Wolfgang Jahnke、Luc Brunsveld、Michelle R. Arkin、Christian Ottmann

  DOI：10.1021/jacs.8b11658

  日期：2019.2.27

  Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3 sigma and a peptide derived from Estrogen Receptor alpha (ER alpha), an important breast cancer target that is negatively regulated by 14-3-3 sigma. We identify orthosteric stabilizers that increase 14-3-3/ER alpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ER alpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.