N-(2-氯苯基)-4-(2-(4-(2-(4-乙基哌嗪-1-基)-2-氧代乙基)苯基氨基)-5-氟嘧啶-4-基氨基)苯甲酰胺 | 1158838-45-9

• 物质功能分类: 生物化工 - 抑制剂 - 细胞周期(Cell Cycle)
• 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: N-(2-氯苯基)-4-(2-(4-(2-(4-乙基哌嗪-1-基)-2-氧代乙基)苯基氨基)-5-氟嘧啶-4-基氨基)苯甲酰胺
• 中文别名: AURORAA抑制剂(AURORAAINHIBITORI)；N-(2-氯苯基)-4-[[2-[[4-[2-(4-乙基-1-哌嗪基)-2-氧代乙基]苯基]氨基]-5-氟-4-嘧啶基]氨基]苯甲酰胺
• 英文名称: aurora A inhibitor I
• 英文别名: TC-S 7010；N-(2-Chlorophenyl)-4-((2-((4-(2-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)benzamide；N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]anilino]-5-fluoropyrimidin-4-yl]amino]benzamide
• CAS: 1158838-45-9
• 化学式: C₃₁H₃₁ClFN₇O₂
• 分子量: 588.084
• InChiKey: AKSIZPIFQAYJGF-UHFFFAOYSA-N

物化性质

• 密度：
  1.362
• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• WGK Germany：
  3

制备方法与用途

生物活性

Aurora A Inhibitor I 是一种新型有效的、选择性 Aurora A 抑制剂，在无细胞试验中的 IC50 值为 3.4 nM，对 Aurora A 的选择性比对 Aurora B 高 1000 倍。此外，它在抑制 HCT116 细胞增殖方面表现优异，IC50 为 0.19 μM；而对 HCT29 细胞作用效果不明显，其 IC50 值达到 2.9 μM。

体外研究

Aurora A Inhibitor I 在抑制 Aurora A 方面比抑制 Aurora B 高出 1000 倍的选择性。然而，它对突变型 Aurora A (T217E) 的作用效果有限。关键氨基酸 Thr217 决定了 Aurora A 对抑制剂的选择性高于 Aurora B。此外，Aurora A Inhibitor I 可使 KCL-22 细胞在 G2/M 期积累，并诱导组蛋白 H3 在 serine 10 位点的磷酸化以及有丝分裂中 Aurora A 的 threonine 288 自磷酸化。5 μM 的浓度下，Aurora A Inhibitor I 显著诱导 KCL-22 细胞凋亡，并使细胞对 imatinib 诱导的凋亡更为敏感。

在 KG-1 和 HL-60 细胞中，Aurora A Inhibitor I 也表现出生长抑制效果。然而，在正常细胞系 WI38 中也观察到其作用。此外，1 μM 的 Aurora A Inhibitor I 可阻断 BCR-ABL 突变的形成，并能对抗 imatinib、nilotinib 或 dasatinib 治疗后 KCL-22 复发及突变体集落。

特征

Aurora A Inhibitor I 是一种 2,4-二苯胺嘧啶抑制剂。在无细胞试验中，其 IC50 值为 3.4 nM，并通过 ROS 介导的 UPR 信号通路触发凋亡。

靶点

Target	Value
Aurora A (Cell-free assay)	3.4 nM

体外研究（重复内容）

Aurora A Inhibitor I 在抑制 Aurora A 方面比抑制 Aurora B 高出 1000 倍的选择性。然而，它对突变型 Aurora A (T217E) 的作用效果有限。关键氨基酸 Thr217 决定了 Aurora A 对抑制剂的选择性高于 Aurora B。此外，Aurora A Inhibitor I 可使 KCL-22 细胞在 G2/M 期积累，并诱导组蛋白 H3 在 serine 10 位点的磷酸化以及有丝分裂中 Aurora A 的 threonine 288 自磷酸化。5 μM 的浓度下，Aurora A Inhibitor I 显著诱导 KCL-22 细胞凋亡，并使细胞对 imatinib 诱导的凋亡更为敏感。

在 KG-1 和 HL-60 细胞中，Aurora A Inhibitor I 也表现出生长抑制效果。然而，在正常细胞系 WI38 中也观察到其作用。此外，1 μM 的 Aurora A Inhibitor I 可阻断 BCR-ABL 突变的形成，并能对抗 imatinib、nilotinib 或 dasatinib 治疗后 KCL-22 复发及突变体集落。

反应信息

• 作为产物：
  描述：

  N-乙基哌嗪 、 4-[[4-[[4-[[(2-氯苯基)氨基]羰基]苯基] 氨基]-5-氟-2-嘧啶]氨基]苯乙酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以78%的产率得到N-(2-氯苯基)-4-(2-(4-(2-(4-乙基哌嗪-1-基)-2-氧代乙基)苯基氨基)-5-氟嘧啶-4-基氨基)苯甲酰胺
  参考文献：
  名称：

  A Class of 2,4-Bisanilinopyrimidine Aurora A Inhibitors with Unusually High Selectivity against Aurora B

  摘要：

  The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.

  DOI：

  10.1021/jm9000314

文献信息

• [EN] DIAMINOPYRIMIDINE BENZENESULFONE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE DIAMINOPYRIMIDINE BENZÈNESULFONE ET LEURS UTILISATIONS
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2015117053A1

  公开（公告）日：2015-08-06

  The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), and pharmaceutically compositions thereof. Compounds of Formula (II) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

  本发明提供了式（II）的化合物（例如，式（I）的化合物）及其药物组合物。式（II）的化合物被认为是结合溴域和/或含溴域蛋白质（例如，溴和额外终端（BET）蛋白质）的结合物。还提供了使用这些化合物和药物组合物的方法、用途和工具箱，用于抑制溴域和/或含溴域蛋白质的活性（例如，增加活性），以及用于治疗和/或预防与溴域或含溴域蛋白质相关的疾病（例如，增殖性疾病、心血管疾病、病毒感染、纤维病性疾病、代谢性疾病、内分泌疾病和辐射中毒）。这些化合物、药物组合物和工具箱也可用于男性避孕。
• Method for identification of anti-HIV human miRNA mimics and miRNA inhibitors and anti-HIV pharmaceutical compounds
  申请人：CSIR

  公开号：US10351916B2

  公开（公告）日：2019-07-16

  The present invention relates to methods for the identification of anti-HIV miRNAs and anti-HIV pharmaceutical compounds using high-throughput screening methods, comprising: transfecting reporter cells with a panel of miRNAs, infecting the reporter cells with HIV, screening the cells to identify miRNAs that modulate HIV infection and identifying the specific pathways, nucleic acids and/or polypeptides that are targeted by the miRNAs. The invention further provides for the identification and screening of anti-HIV pharmaceutical compounds having known activity against the specific pathways, nucleic acids and/or polypeptides that are targeted by the miRNAs for efficacy in the treatment of HIV. The invention also provides for the use of miRNA mimics, miRNA inhibitors and pharmaceutical compounds (including oncology drugs and kinase inhibitors) in the treatment and/or prevention of HIV infection.

  本发明涉及利用高通量筛选方法鉴定抗HIV miRNA和抗HIV药物化合物的方法，包括：用一组miRNA转染报告细胞，用HIV感染报告细胞，筛选细胞以鉴定调节HIV感染的miRNA，鉴定miRNA靶向的特定通路、核酸和/或多肽。本发明进一步提供了鉴定和筛选抗 HIV 药物化合物的方法，这些化合物对 miRNAs 靶向的特定途径、核酸和/或多肽具有已知的活性，可有效治疗 HIV。本发明还提供了 miRNA 模拟物、miRNA 抑制剂和药物化合物（包括肿瘤药物和激酶抑制剂）在治疗和/或预防 HIV 感染中的用途。
• Combination therapy of transcription inhibitors and kinase inhibitors
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10702527B2

  公开（公告）日：2020-07-07

  The present disclosure provides combination therapy of a transcription inhibitor and a kinase inhibitor. The combination of the transcription inhibitor and the kinase inhibitor may be useful in treating and/or preventing in a subject a proliferative disease, such as proliferative a disease that is resistant to the transcription inhibitor alone or the kinase inhibitor alone. In certain embodiments, the proliferative disease is a cancer. The combination of the transcription inhibitor and the kinase inhibitor is expected to be synergistic.

  本公开提供了转录抑制剂和激酶抑制剂的组合疗法。转录抑制剂和激酶抑制剂的组合可用于治疗和/或预防受试者的增殖性疾病，如对单独转录抑制剂或单独激酶抑制剂耐药的增殖性疾病。在某些实施方案中，增殖性疾病是癌症。转录抑制剂和激酶抑制剂的组合可望产生协同作用。
• Diaminopyrimidine benzenesulfone derivatives and uses thereof
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10730860B2

  公开（公告）日：2020-08-04

  The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), and pharmaceutically compositions thereof. Compounds of Formula (II) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

  本发明提供了式(II)化合物（如式(I)化合物）及其药用组合物。据信，式（II）化合物是溴结构域和/或含溴结构域蛋白质（如溴外末端（BET）蛋白质）的结合剂。还提供了使用这些化合物和药物组合物的方法、用途和试剂盒，这些化合物和药物组合物用于抑制溴基链和/或含溴基链蛋白的活性（如活性增加），并用于治疗和/或预防受试者与溴基链或含溴基链蛋白相关的疾病（如增殖性疾病、心血管疾病、病毒感染、纤维化疾病、代谢性疾病、内分泌疾病和辐射中毒）。这些化合物、药物组合物和试剂盒还可用于男性避孕。
• COMPOSITIONS AND METHODS FOR TREATING A CLINICAL CONDITION THROUGH THE USE OF HEMATOPOIETIC STEM CELLS
  申请人：Indiana University Research & Technology Corporation

  公开号：EP3638268A1

  公开（公告）日：2020-04-22