5-bromo-N-(4-(pyrrolidinyl)piperidinyl)nicotinamide trifluoroacetic acid | 1287287-05-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-bromo-N-(4-(pyrrolidinyl)piperidinyl)nicotinamide trifluoroacetic acid
• 英文别名: UNC669
• CAS: 1287287-05-1
• 化学式: C₂HF₃O₂*C₁₅H₂₀BrN₃O
• 分子量: 452.271
• InChiKey: RRWRFFFUMAIDSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.18
• 重原子数：
  27.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  73.74
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  （5-溴-3-吡啶基）[4-（1-吡咯烷基）-1-哌啶基]甲酮 、 三氟乙酸 以 二氯甲烷 为溶剂， 以123 mg的产率得到5-bromo-N-(4-(pyrrolidinyl)piperidinyl)nicotinamide trifluoroacetic acid
  参考文献：
  名称：

  Small-Molecule Ligands of Methyl-Lysine Binding Proteins

  摘要：

  Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small-molecule MBT antagonists were designed based on the structure of histone peptide - MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first cocrystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.

  DOI：

  10.1021/jm200045v

文献信息

• Rational Adaptation of L3MBTL1 Inhibitors to Create Small‐Molecule Cbx7 Antagonists
  作者：Chakravarthi Simhadri、Kevin D. Daze、Sarah F. Douglas、Natalia Milosevich、Leticia Monjas、Amarjot Dev、Tyler M. Brown、Anna K. H. Hirsch、Jeremy E. Wulff、Fraser Hof

  DOI：10.1002/cmdc.201900021

  日期：2019.8.6

  homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low‐molecular‐weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors

  Chromobox homolog 7（Cbx7）是一种表观遗传调节剂，是多种癌症的重要驱动因素。它是一种甲基阅读器蛋白，通过识别并结合特定伴侣上的甲基化赖氨酸残基来发挥作用。本文中，我们报告了我们的工作，即通过对另一种甲基阅读器蛋白L3MBTL1的抑制剂进行合理的结构改造，从而创造出Cbx7的低分子量抑制剂，该抑制剂以前据报道对Cbx7没有活性。我们通过荧光偏振分析评估了每种新抑制剂对Cbx7的抑制作用，并且还通过饱和转移差NMR光谱法确认了所选抑制剂与Cbx7的结合。这项工作识别的多个小分子抑制剂具有适度（IC 50：257-500μ米）的效力。