4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide
• 化学式: C₁₂H₁₃N₃O₃
• mdl: MFCD22260861
• 分子量: 247.254
• InChiKey: JBOKBLSWHXNCMS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation

  摘要：

  DOI：

  10.1021/acs.jmedchem.3c01848

文献信息

• Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs
  作者：Christian Steinebach、Aleša Bricelj、Arunima Murgai、Izidor Sosič、Luca Bischof、Yuen Lam Dora Ng、Christopher Heim、Samuel Maiwald、Matic Proj、Rabea Voget、Felix Feller、Janez Košmrlj、Valeriia Sapozhnikova、Annika Schmidt、Maximilian Rudolf Zuleeg、Patricia Lemnitzer、Philipp Mertins、Finn K. Hansen、Michael Gütschow、Jan Krönke、Marcus D. Hartmann

  DOI：10.1021/acs.jmedchem.3c00851

  日期：2023.11.9

  develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders

  沙利度胺、泊马度胺和来那度胺等免疫调节酰亚胺药物 (IMiD) 是蛋白水解靶向嵌合体 (PROTAC) 设计中最常见的 cereblon (CRBN) 招募剂。然而，这些 CRBN 配体会诱导 IMiD 新底物的降解，并且本质上不稳定，在温和条件下会水解降解。在这项工作中，我们同时优化了理化性质、稳定性、靶向亲和力和脱靶新底物调节特征，以开发新型非邻苯二甲酰亚胺 CRBN 粘合剂。这些努力导致了构象锁定苯甲酰胺型衍生物的发现，这些衍生物复制了天然 CRBN 降解决定子的相互作用，表现出增强的化学稳定性，并在新底物招募方面表现出良好的选择性。最有效的配体的效用通过它们转化为 BRD4 和 HDAC6 的有效降解剂而得到证明，其性能优于先前描述的参考 PROTAC。加上它们对 IKZF1/3 和 SALL4 的新生连接酶活性显着降低，这些配体为设计高选择性和有效的化学惰性邻近诱导化合物提供了机会。
• A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders
  作者：Ka Yang、Yu Zhao、Xueqing Nie、Hao Wu、Bo Wang、Chelsi M. Almodovar-Rivera、Haibo Xie、Weiping Tang

  DOI：10.1016/j.chembiol.2020.04.008

  日期：2020.7

  Proteolysis-targeting chimeras (PROTACs) is a paradigm shift for small-molecule drug discovery. However, limited E3 ubiquitin ligase ligands with cellular activity are available. In vitro binding assays involve the expression and purification of a large amount of proteins and they often yield ligands that are inactive in cell-based assays due to poor cell permeability, stability, and other reasons. Herein, we report the development of a practical and efficient cell-based target engagement assay to evaluate the binding affinity of a small library of cereblon ligands to its E3 ligase in cells. Selected cell-permeable E3 ligase ligands derived from this assay are then used to construct HDAC6 degraders with cellular protein degradation activity. Because the assay does not involve any genetic engineering, it is relatively easy to transfer from one cell type to a different one.