3-((5-bromo-2-hydroxyphenyl)sulfonamido)-5-(1-cyanocyclobutyl)-2-hydroxybenzoic acid

• 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-((5-bromo-2-hydroxyphenyl)sulfonamido)-5-(1-cyanocyclobutyl)-2-hydroxybenzoic acid
• 英文别名: 3-[(5-Bromo-2-hydroxyphenyl)sulfonylamino]-5-(1-cyanocyclobutyl)-2-hydroxybenzoic acid；3-[(5-bromo-2-hydroxyphenyl)sulfonylamino]-5-(1-cyanocyclobutyl)-2-hydroxybenzoic acid
• 化学式: C₁₈H₁₅BrN₂O₆S
• 分子量: 467.297
• InChiKey: BLJKTQGNFJGAOA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  156
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-溴-4-甲氧基苯乙腈 在 吡啶 、 5%-palladium/activated carbon 、 四丁基溴化铵 、 氢气 、 硝酸 、 palladium diacetate 、 三溴化硼 、 sodium hydride 、 三乙胺 、 lithium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 、 苯酚 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 1,2-二氯乙烷 、 乙腈 、 mineral oil 为溶剂， -78.0~90.0 ℃ 、101.33 kPa 条件下， 反应 67.0h， 生成 3-((5-bromo-2-hydroxyphenyl)sulfonamido)-5-(1-cyanocyclobutyl)-2-hydroxybenzoic acid
  参考文献：
  名称：

  Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction

  摘要：

  The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.

  DOI：

  10.1021/acs.jmedchem.9b01411

文献信息

• [EN] WDR5-MYC INHIBITORS<br/>[FR] INHIBITEURS DE WDR5-MYC
  申请人：UNIV VANDERBILT

  公开号：WO2021021951A1

  公开（公告）日：2021-02-04

  Substituted N-phenyl sulfonamide compounds inhibit WDR5-MYC interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.

  取代的N-苯基磺酰胺化合物可以抑制WDR5-MYC相互作用，这些化合物及其药物组合物可用于治疗受试者中的疾病和状况，如癌细胞增殖。
• Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction
  作者：Jonathan D. Macdonald、Selena Chacón Simon、Changho Han、Feng Wang、J. Grace Shaw、Jennifer E. Howes、Jiqing Sai、Joannes P. Yuh、Demarco Camper、Bethany M. Alicie、Joseph Alvarado、Sameer Nikhar、William Payne、Erin R. Aho、Joshua A. Bauer、Bin Zhao、Jason Phan、Lance R. Thomas、Olivia W. Rossanese、William P. Tansey、Alex G. Waterson、Shaun R. Stauffer、Stephen W. Fesik

  DOI：10.1021/acs.jmedchem.9b01411

  日期：2019.12.26

  The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.