4-[[(4-环己基苯基)甲基][2-[甲基[(2,3,4,5,6-五氟苯基)磺酰基]氨基]乙酰基]氨基]-2-羟基苯甲酸 | 1334493-07-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-[[(4-环己基苯基)甲基][2-[甲基[(2,3,4,5,6-五氟苯基)磺酰基]氨基]乙酰基]氨基]-2-羟基苯甲酸
• 中文别名: 化合物BP-1-102；转录因子STAT3小分子抑制剂(BP-1-102)；BP-1-102游离态
• 英文名称: BP-1-102
• 英文别名: 4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido)-2-hydroxybenzoic acid；4-[(4-cyclohexylphenyl)methyl-[2-[methyl-(2,3,4,5,6-pentafluorophenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid
• CAS: 1334493-07-0
• 化学式: C₂₉H₂₇F₅N₂O₆S
• 分子量: 626.601
• InChiKey: WNVSFFVDMUSXSX-UHFFFAOYSA-N

物化性质

• 沸点：
  749.2±70.0 °C(Predicted)
• 密度：
  1.474±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO:15.0(最大浓度 mg/mL);23.9(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  12

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20℃

制备方法与用途

生物活性

BP-1-102 是一种对转录因子 STAT3 具有口服活性的小分子抑制剂，其 IC50 值为 6.8 μM。

靶点

| STAT3 | 6.8 μM (IC50) |

体外研究

BP-1-102 与 Stat3 的结合亲和力 Kd 为 504 nM，并以 6.8±0.8 μM 的 IC50 值抑制了 Stat3 的 DNA 结合活性。该化合物在 4-6.8 μM 浓度下阻断了 Stat3 磷酸酪氨酸肽的相互作用及 STAT3 活化，并选择性地抑制了依赖 STAT3 的肿瘤细胞的生长、存活、迁移和侵袭。BP-1-102 能抑制肿瘤细胞中异常活化的 STAT3，从而抑制 c-Myc、Cyclin D1、Bcl-xL、Survivin、VEGF 和 Krüppel-like factor 8 的表达。

体内研究

给予小鼠治疗剂量的 BP-1-102（一种针对 STAT3/NF-kB 激活及其相互作用的口服生物活性化合物），可减少结肠肿瘤的发生，并降低肿瘤区域 STAT3/NF-kB 活化细胞因子的表达。BP-1-102 口服后在肿瘤组织中积累至足以抑制异常活化的 Stat3 功能并抑制肿瘤生长的水平。

反应信息

• 作为反应物：
  描述：

  4-[[(4-环己基苯基)甲基][2-[甲基[(2,3,4,5,6-五氟苯基)磺酰基]氨基]乙酰基]氨基]-2-羟基苯甲酸 、 乙酸酐 在 硫酸 作用下， 以60%的产率得到2-acetoxy-4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido) benzoic acid
  参考文献：
  名称：

  Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

  摘要：

  The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K-D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

  DOI：

  10.1021/ml4003138
• 作为产物：
  描述：

  4-氨基水杨酸 在 palladium 10% on activated carbon 、 potassium tert-butylate 、 氢气 、 sodium cyanoborohydride 、 溶剂黄146 、 三苯基二氯化膦 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.66h， 生成 4-[[(4-环己基苯基)甲基][2-[甲基[(2,3,4,5,6-五氟苯基)磺酰基]氨基]乙酰基]氨基]-2-羟基苯甲酸
  参考文献：
  名称：

  Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

  摘要：

  The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K-D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

  DOI：

  10.1021/ml4003138

文献信息

• [EN] STAT DEGRADERS AND USES THEREOF<br/>[FR] AGENTS DE DÉGRADATION DE STAT ET LEURS UTILISATIONS
  申请人：KYMERA THERAPEUTICS INC

  公开号：WO2020206424A1

  公开（公告）日：2020-10-08

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用方法。
• Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
  申请人：University of Central Florida Research Foundation, Inc.

  公开号：US10196373B2

  公开（公告）日：2019-02-05

  In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代的2-羟基-4-(2-(苯磺酰胺基)乙酰胺基)苯甲酸类似物，其衍生物和相关化合物，这些化合物可用作STAT蛋白活性的抑制剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与STAT蛋白活性功能障碍相关的细胞不受控制增殖疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不打算限制本发明。
• [EN] METHODS OF TARGETING APE1/REF-1 TO INHIBIT HYPOXIA SIGNALING GENES<br/>[FR] PROCÉDÉS DE CIBLAGE D'APE1/REF -1 POUR INHIBER LES GÈNES DE SIGNALISATION DE L'HYPOXIE
  申请人：UNIV INDIANA RES & TECH CORP

  公开号：WO2016186853A1

  公开（公告）日：2016-11-24

  Methods for targeting apurinic/apyrimidinic endonuclease1/redox effector factor 1 (APEl/Ref-1) are disclosed. More particularly, methods for inhibiting APEl/Ref-1 and hypoxia-mediated signaling for decreasing survival and invasion of tumor cells exposed to hypoxic conditions are disclosed.

  本发明揭示了用于靶向apurinic / apyrimidinic内切酶1 / 氧化还原效应因子1（APEl / Ref-1）的方法。更具体地，揭示了用于抑制APEl / Ref-1和缺氧介导的信号传导的方法，以减少暴露于缺氧条件下的肿瘤细胞的生存和侵袭。
• SUBSTITUTED 2-HYDROXY-4-(2-(PHENYLSULFONAMIDO)ACETAMIDO)BENZOIC ACID ANALOGS AS INHIBITORS OF STAT PROTEIN
  申请人：University of Central Florida Research Foundation, Inc.

  公开号：US20150038708A1

  公开（公告）日：2015-02-05

  In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及替代的2-羟基-4-(2-(苯磺酰胺)乙酰胺)苯甲酸类似物、其衍生物和相关化合物，它们可以作为STAT蛋白活性的抑制剂；制备这些化合物的合成方法；包含这些化合物的制药组合物；以及使用这些化合物和组合物治疗与STAT蛋白活性功能障碍相关的细胞增殖失控症状的方法。本摘要旨在作为特定领域搜索的扫描工具，不意味着对本发明的限制。
• SALICYCLIC ACID DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, COMPOSITION THEREOF AND METHOD OF USE THEREOF
  申请人：The Governing Council of the University of Toronto

  公开号：US20150158894A1

  公开（公告）日：2015-06-11

  The present invention relates to novel compounds, compositions containing same and methods for inhibiting STAT3 and/or STAT5 activity or for the treatment of a STAT3 or STAT5-dependent cancer using said compounds; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  本发明涉及新型化合物、含有该化合物的组合物以及使用该化合物抑制STAT3和/或STAT5活性或治疗STAT3或STAT5依赖性癌症的方法；或其药学上可接受的盐、溶剂或前药。