LDN-209929 | 1233355-57-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: LDN-209929
• 英文别名: 3-((2-chloro-7-methoxyacridin-9-yl)thio)propan-1-amine；3-(2-Chloro-7-methoxyacridin-9-yl)sulfanylpropan-1-amine
• CAS: 1233355-57-1
• 化学式: C₁₇H₁₇ClN₂OS
• 分子量: 332.854
• InChiKey: XMMAOXMYUGQGJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  73.4
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

生物活性

LDN-209929 dihydrochloride 是一种有效且选择性的 haspin kinase 抑制剂 (IC50=55 nM)，对 DYRK2 的选择性为 180 倍 (IC50=9.9 μM)。它是在 LDN-192960（HY-13455）的基础上优化得到的。

靶点

• IC50: 55 nM （haspin kinase）
• IC50: 9.9 μM （DYRK2）

体外研究

• Haspin: Haploid Germ Cell-Specific Nuclear Protein Kinase 是一种丝氨酸/苏氨酸激酶，在多种组织（如睾丸、骨髓、胸腺和脾脏）中表达。Haspin 在有丝分裂过程中也发挥重要作用，它在 G2/早期前期磷酸化组蛋白 H3 的 Thr-3 (H3T3)，在前期中期达到最大值，并在后期逐渐减少。
• DYRKs: 属于 CMGC 家族的 ePKs，可以进一步分为 DYRK1A 和 1B 类激酶以及 DYRK2、3 和 4 类激酶。DYRKs 的活性依赖于合成过程中必需激活环酪氨酸的自磷酸化。

反应信息

• 作为产物：
  描述：

  在 盐酸 、 甲醇 作用下， 以 1,4-二氧六环 为溶剂， 生成 LDN-209929
  参考文献：
  名称：

  Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors

  摘要：

  Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC(50) <60 nM) with 180fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC(50) <400 nM) with a 5.4-fold selectivity over haspin was also identified. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.04.150

文献信息

• Acridines As Inhibitors Of Haspin And DYRK Kinases
  申请人：Higgins Jonathan

  公开号：US20130102627A1

  公开（公告）日：2013-04-25

  The present disclosure is directed to compounds of Formula I: which are inhibitors of Haspin kinase and DYRK kinases. The compounds of the present disclosure, and compositions thereof, are useful in the treatment of disease related to Haspin kinase and DYRK kinase expression and/or activity.

  本公开涉及I式化合物，它们是Haspin激酶和DYRK激酶的抑制剂。本公开的化合物及其组合物在治疗与Haspin激酶和DYRK激酶表达和/或活性相关的疾病方面是有用的。
• [EN] ACRIDINES AS INHIBITORS OF HASPIN AND DYRK KINASES<br/>[FR] ACRIDINES EN TANT QU'INHIBITEURS DES KINASES HASPINE ET DYRK
  申请人：BRIGHAM & WOMENS HOSPITAL

  公开号：WO2011127406A2

  公开（公告）日：2011-10-13

  The present disclosure is directed to compounds of Formula I: which are inhibitors of Haspin kinase and DYRK kinases. The compounds of the present disclosure, and compositions thereof, are useful in the treatment of disease related to Haspin kinase and DYRK kinase expression and/or activity.
• Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors
  作者：Gregory D. Cuny、Maxime Robin、Natalia P. Ulyanova、Debasis Patnaik、Valerie Pique、Gilles Casano、Ji-Feng Liu、Xiangjie Lin、Jun Xian、Marcie A. Glicksman、Ross L. Stein、Jonathan M.G. Higgins

  DOI：10.1016/j.bmcl.2010.04.150

  日期：2010.6

  Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC(50) <60 nM) with 180fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC(50) <400 nM) with a 5.4-fold selectivity over haspin was also identified. (C) 2010 Elsevier Ltd. All rights reserved.