TX1-85-1 | 1603845-32-4

• 物质功能分类: 生物 - 生化试剂盒
• 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: TX1-85-1
• 英文别名: N-[5-[1-[4-(4-acetylpiperazin-1-yl)cyclohexyl]-4-aminopyrazolo[3,4-d]pyrimidin-3-yl]-2-phenoxyphenyl]prop-2-enamide
• CAS: 1603845-32-4
• 化学式: C₃₂H₃₆N₈O₃
• 分子量: 580.69
• InChiKey: FYICDSWKKFSYOM-UHFFFAOYSA-N

物化性质

• 沸点：
  825.5±65.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：0.2 mg/ml；二甲基亚砜：0.2 mg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  8

制备方法与用途

生物活性

TX1-85-1 是一种不可逆的 Her3 (ErbB3) 抑制剂，其 IC50 值为 23 nM。TX1-85-1 是第一个选择性 Her3 配体，能够与位于 Her3 的 ATP 结合位点上的 Cys721 形成共价键。这种抑制剂可以诱导 Her3 蛋白的部分降解，并减弱依赖 Her3 信号传导。

目标靶点

• ErbB3
• IC50: 23 nM

体外研究

TX1-85-1 在不同细胞系中的抗增殖 EC50 值分别为：Ovcar8 细胞为 9.9 μM、HCC827 GR6 细胞为 11.5 μM 和 PC9 GR4 细胞为 16.9 μM。

反应信息

• 作为产物：
  描述：

  4-羟基环己酮乙二醇缩醛 在 bis-triphenylphosphine-palladium(II) chloride 、 氢气 、 三乙酰氧基硼氢化钠 、 碳酸氢钠 、 potassium carbonate 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 TX1-85-1
  参考文献：
  名称：

  Development of small molecules targeting the pseudokinase Her3

  摘要：

  Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.04.103

文献信息

• METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20160176916A1

  公开（公告）日：2016-06-23

  The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

  本申请提供了作为蛋白质降解诱导基团的双功能化合物。本申请还涉及通过使用将结合脑白质蛋白的基团与能够结合到靶向蛋白的配体相连的双功能化合物来实现内源蛋白的靶向降解的方法，该方法可用于治疗增殖性疾病。本申请还提供了制备本申请化合物及其中间体的方法。
• [EN] HYDROPHOBICALLY TAGGED SMALL MOLECULES AS INDUCERS OF PROTEIN DEGRADATION<br/>[FR] PETITES MOLÉCULES MARQUÉES DE FAÇON HYDROPHOBE EN TANT QU'INDUCTEURS DE LA DÉGRADATION DE PROTÉINE
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2014063061A1

  公开（公告）日：2014-04-24

  Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L1 represents a linker; and RH represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.

  提供了化学式(I)的双功能小分子，或其药用盐，其中M代表一个小有机分子，可以共价或非共价结合激酶，如Her3蛋白激酶；L1代表一个连接物；RH代表一个疏水基团。化合物化学式(I)的一个例子是化合物化学式(II)。还提供了包含化学式(I)或(II)的药物组合物，以及使用这些化合物治疗增殖性疾病的方法。
• HYDROPHOBICALLY TAGGED SMALL MOLECULES AS INDUCERS OF PROTEIN DEGRADATION
  申请人：DANA-FARBER CANCER INSTITUTE, INC.

  公开号：US20150274738A1

  公开（公告）日：2015-10-01

  Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L 1 represents a linker; and R H represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.

  提供的是公式（I）的双功能小分子或其药学上可接受的盐，其中M代表结合激酶的小有机分子，可以是共价或非共价结合，例如Her3蛋白激酶；L1代表连接物；RH代表疏水基团。公式（I）的一个化合物示例是公式（II）的化合物： 还提供了包含公式（I）或（II）化合物的药物组合物，以及使用这些化合物治疗增殖性疾病的方法。
• Methods to induce targeted protein degradation through bifunctional molecules
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10669253B2

  公开（公告）日：2020-06-02

  The present application provides bifunctional compounds which act as SMARCA2 and Ras protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of SMARCA2 and Ras through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to SMARCA2 or Ras. The application also provides compounds of Formula:

  本申请提供了作为SMARCA2和Ras蛋白降解诱导分子的双功能化合物。本申请还涉及通过使用将脑龙结合分子与能够与 SMARCA2 或 Ras 结合的配体连接的双官能化合物来靶向降解 SMARCA2 和 Ras 的方法。本申请还提供了式化合物：
• PROTEIN DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20210002296A1

  公开（公告）日：2021-01-07

  The present invention provides compounds, compositions thereof, and methods of using the same for the targeted degradation of proteins, and the treatment of target protein-mediated disorders.