5-amino-N-(4'-amino-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-2-chloro-4-fluoro-3-methylbenzamide

• 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: 5-amino-N-(4'-amino-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-2-chloro-4-fluoro-3-methylbenzamide
• 英文别名: 5-amino-N-[5-(4-aminophenyl)-2-(4-methylpiperazin-1-yl)phenyl]-2-chloro-4-fluoro-3-methylbenzamide
• 化学式: C₂₅H₂₇ClFN₅O
• 分子量: 467.974
• InChiKey: HVMNEZGNJGWWQS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  87.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-amino-N-(4'-amino-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-2-chloro-4-fluoro-3-methylbenzamide 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 5-amino-N-(4'-(2-aminoacetamido)-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-2-chloro-4-fluoro-3-methylbenzamide
  参考文献：
  名称：

  High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity

  摘要：

  MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 mu M) in HMT assay. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.036
• 作为产物：
  描述：

  2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride 在 吡啶 、 tin(ll) chloride 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 10.0h， 生成 5-amino-N-(4'-amino-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-2-chloro-4-fluoro-3-methylbenzamide
  参考文献：
  名称：

  发现具有体内抗肿瘤活性的有效 MLL1 和 WDR5 蛋白-蛋白相互作用抑制剂

  摘要：

  MLL1-WDR5 相互作用对于 MLL 核心复合物的形成及其 H3K4 甲基转移酶活性至关重要。已经提出破坏 MLL1-WDR5 相互作用作为治疗白血病的潜在治疗方法。具有良好特征的化学探针的“工具包”将允许探索动物研究。基于我们小组先前报道的特定 MLL-WDR5 PPI 抑制剂 ( DDO-2117 )，我们通过点击化学进行了支架跳跃方法，以发现新型苯基三唑支架 MLL1-WDR5 相互作用阻断剂。在这里，我们的努力产生了最好的抑制剂24 ( DDO-2093 )，它具有高结合亲和力 (K d  = 11.6 nM) 并具有改进的类药物特性。无论在体外和体内试验显示24可以有效地阻断 MLL1-WDR5 相互作用。此外，24显着抑制了 MV4-11 异种移植小鼠模型中的肿瘤生长，并显示出良好的安全性。我们建议将24作为一种化学探针，适用于MLL1-WDR5 相互作用的体内药效学和生物学研究。

  DOI：

  10.1016/j.ejmech.2021.113677

文献信息

• COMPOSITIONS AND METHODS FOR INHIBITING PHENYL TRIAZOLE MLL1-WDR5 PROTEIN-PROTEIN INTERACTION
  申请人：China Pharmaceutical University

  公开号：US20210139466A1

  公开（公告）日：2021-05-13

  The present disclosure relates to the field of medicinal chemistry, in particular to a phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor (I) and a preparation method thereof, and pharmacodynamics experiments prove that the compound of the present disclosure has relatively strong MLL1-WDR5 protein-protein interaction inhibition activity.
• ANILINE-BASED WDR5 PROTEIN-PROTEIN INTERACTION INHIBITOR, AND PREPARATION METHOD AND USE THEREOF
  申请人：CHINA PHARMACEUTICAL UNIVERSITY

  公开号：US20220152027A1

  公开（公告）日：2022-05-19

  The present disclosure discloses a WDR5 protein-protein interaction inhibitor, including a compound having a structure represented by general formula (I). Experiments show that the inhibitor acts on a WDR5 protein and an interacting protein thereof including, but not limited to, MLL, selectively inhibits the proliferation of leukemia cells, and inhibits the methylation of H3K4 and the expression of downstream Hox/Meis-1 gene at the cellular level. The present disclosure also discloses a method for preparing the inhibitor and use thereof in the preparation of a drug for treating acute leukemia and other related diseases.
• High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity
  作者：Dong-Dong Li、Wei-Lin Chen、Zhi-Hui Wang、Yi-Yue Xie、Xiao-Li Xu、Zheng-Yu Jiang、Xiao-Jin Zhang、Qi-Dong You、Xiao-Ke Guo

  DOI：10.1016/j.ejmech.2016.08.036

  日期：2016.11

  MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 mu M) in HMT assay. (C) 2016 Elsevier Masson SAS. All rights reserved.
• Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity
  作者：Weilin Chen、Xin Chen、Dongdong Li、Xianghan Wang、Guanlu Long、Zhengyu Jiang、Qidong You、Xiaoke Guo

  DOI：10.1016/j.ejmech.2021.113677

  日期：2021.11

  by click chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft

  MLL1-WDR5 相互作用对于 MLL 核心复合物的形成及其 H3K4 甲基转移酶活性至关重要。已经提出破坏 MLL1-WDR5 相互作用作为治疗白血病的潜在治疗方法。具有良好特征的化学探针的“工具包”将允许探索动物研究。基于我们小组先前报道的特定 MLL-WDR5 PPI 抑制剂 ( DDO-2117 )，我们通过点击化学进行了支架跳跃方法，以发现新型苯基三唑支架 MLL1-WDR5 相互作用阻断剂。在这里，我们的努力产生了最好的抑制剂24 ( DDO-2093 )，它具有高结合亲和力 (K d  = 11.6 nM) 并具有改进的类药物特性。无论在体外和体内试验显示24可以有效地阻断 MLL1-WDR5 相互作用。此外，24显着抑制了 MV4-11 异种移植小鼠模型中的肿瘤生长，并显示出良好的安全性。我们建议将24作为一种化学探针，适用于MLL1-WDR5 相互作用的体内药效学和生物学研究。