(R)-N-(2-amino-4-fluorophenyl)-6-(3-methyl-2-phenylbutanamido)nicotinamide

• 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: (R)-N-(2-amino-4-fluorophenyl)-6-(3-methyl-2-phenylbutanamido)nicotinamide
• 英文别名: N-(2-amino-4-fluorophenyl)-6-[[(2R)-3-methyl-2-phenylbutanoyl]amino]pyridine-3-carboxamide
• 化学式: C₂₃H₂₃FN₄O₂
• 分子量: 406.46
• InChiKey: GYRBFGSXTHYTOT-OAQYLSRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  97.1
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-氨基烟酸甲酯 在 水 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 (R)-N-(2-amino-4-fluorophenyl)-6-(3-methyl-2-phenylbutanamido)nicotinamide
  参考文献：
  名称：

  Targeting breast cancer stem cells by novel HDAC3-selective inhibitors

  摘要：

  Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing beta-catenin expression through the Akt/GSM3 beta pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of beta-catenin. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.08.069

文献信息

• COMBINATION OF A SELECTIVE HISTONE DEACETYLASE 3 (HDAC3) INHIBITOR AND AN IMMUNOTHERAPY AGENT FOR THE TREATMENT OF CANCER
  申请人：KDAc Therapeutics, Inc.

  公开号：US20190216754A1

  公开（公告）日：2019-07-18

  Aspects of the disclosure relate to compositions, kits, and methods for the treatment of cancer that utilize a selective histonc deacetylase 3 (HDAC3) inhibitor. In some aspects, the compositions, kits, and methods relate to use of a selective HDAC3 inhibitor in combination with an immunotherapy agent (e.g., an immune checkpoint inhibitor).

  披露的方面涉及使用选择性组蛋白去乙酰化酶3（HDAC3）抑制剂进行癌症治疗的组合物、试剂盒和方法。在某些方面，这些组合物、试剂盒和方法涉及使用选择性HDAC3抑制剂与免疫治疗药物（例如免疫检查点抑制剂）的结合。
• Targeting breast cancer stem cells by novel HDAC3-selective inhibitors
  作者：Hao-Yu Hsieh、Hsiao-Ching Chuang、Fang-Hsiu Shen、Kinjal Detroja、Ling-Wei Hsin、Ching-Shih Chen

  DOI：10.1016/j.ejmech.2017.08.069

  日期：2017.11

  Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing beta-catenin expression through the Akt/GSM3 beta pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of beta-catenin. (C) 2017 Elsevier Masson SAS. All rights reserved.