2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide
• 英文别名: 2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]-N-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethyl]acetamide
• 化学式: C₄₅H₅₃N₁₁O₉
• 分子量: 891.984
• InChiKey: SVMNWGPZVPEEIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  65
• 可旋转键数：
  18
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  238
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  帕布昔利布 在 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide
  参考文献：
  名称：

  靶向靶向嵌合体降解蛋白的CDK6的潜在和优先降解。

  摘要：

  开发了劫持癌症治疗靶标CDK6的重点PROTAC文库。为理解这些PROTAC中的降解曲线差异，提出了一种设计原则，即“匹配/不匹配”。值得注意的是，通过将CDK6抑制剂palbociclib和E3连接酶CRBN募集者pomalidomide连接起来，可产生具有特定且显着的CDK6降解潜能的强效PROTAC。PROTAC强烈抑制包括多发性骨髓瘤在内的造血癌细胞的增殖，并强烈抑制CDK6的拷贝扩增/突变形式的降解，这表明了其未来的潜在临床应用。

  DOI：

  10.1021/acs.jmedchem.9b00871

文献信息

• [EN] DEGRADATION OF CYCLIN-DEPENDENT KINASE 4/6 (CDK4/6) BY CONJUGATION OF CDK4/6 INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE<br/>[FR] DÉGRADATION DE LA KINASE 4/6 CYCLINE-DÉPENDANTE (CDK4/6) PAR CONJUGAISON D'INHIBITEURS DE CDK4/6 AVEC UN LIGAND DE TYPE LIGASE E3 ET LEURS PROCÉDÉS D'UTILISATION
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2017185031A1

  公开（公告）日：2017-10-26

  The present application provides bifunctional compounds of Formula (I), or Targeting Ligand, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 4 (CDK4) and/or cyclin-dependent kinase 6 (CDK6). The present application also relates to methods for the targeted degradation of CDK4 and/or CDK6 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK4 and/or CDK6 which can be utilized in the treatment of disorders modulated by CDK4 and/or CDK6.

  本申请提供了式（I）的双功能化合物，或者靶向配体，或者其药学上可接受的盐、水合物、溶剂合物、前药、立体异构体或互变异构体，这些化合物作为蛋白质降解诱导基团，用于细胞周期依赖性激酶4（CDK4）和/或细胞周期依赖性激酶6（CDK6）。本申请还涉及通过使用将泛素连接酶结合基团与能够结合到CDK4和/或CDK6的配体相连接的双功能化合物来实现CDK4和/或CDK6的靶向降解的方法，该方法可用于治疗由CDK4和/或CDK6调节的疾病。
• [EN] DEGRADATION OF CYCLIN-DEPENDENT KINASE 4/6 (CDK4/6) BY CONJUGATION OF CDK4/6 INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE<br/>[FR] DÉGRADATION DE LA KINASE 4/6 DÉPENDANTE DE LA CYCLINE (CDK4/6) PAR CONJUGAISON D'INHIBITEURS DE CDK4/6 AVEC UN LIGAND DE TYPE LIGASE E3 ET PROCÉDÉS D'UTILISATION
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2020023480A1

  公开（公告）日：2020-01-30

  The present application provides bifunctional compounds, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 4 (CDK4) and/or cyclin-dependent kinase 6 (CDK6). The present application also relates to methods for the targeted degradation of CDK4 and/or CDK6 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK4 and/or

  本申请提供了具有双功能化合物的药物可接受盐、水合物、溶剂合物、前药、立体异构体或互变异构体，这些化合物作为蛋白质降解诱导基团，用于细胞周期依赖性激酶4（CDK4）和/或细胞周期依赖性激酶6（CDK6）。本申请还涉及通过使用将泛素连接酶结合基团与能够结合到CDK4和/或CDK6的配体连接的双功能化合物来实现对CDK4和/或CDK6的靶向降解的方法。
• Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6
  作者：Baishan Jiang、Eric S. Wang、Katherine A. Donovan、Yanke Liang、Eric S. Fischer、Tinghu Zhang、Nathanael S. Gray

  DOI：10.1002/anie.201901336

  日期：2019.5.6

  Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either

  细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 是细胞周期的关键调节因子，FDA 批准了 CDK4/6 抑制剂用于治疗转移性乳腺癌患者。然而，由于其 ATP 结合位点的保护，选择剂的开发仍然难以实现。在这里，我们报告了基于酰亚胺的降解剂分子，能够降解 CDK4/6，或选择性降解 CDK4 或 CDK6。我们还能够调整这些分子针对 Ikaros (IKZF1) 和 Aiolos (IKZF3) 的活性，它们是基于酰亚胺的降解剂的既定目标。我们发现，在套细胞淋巴瘤细胞系中，与 CDK4/6 抑制、CDK4/6 降解或 IKZF1/3 降解相比，IKZF1/3 降解与双重 CDK4/6 降解相结合产生增强的抗增殖作用。总之，我们在此报告了第一个能够诱导 CDK4 和 CDK6 选择性降解的化合物，作为药理学剖析其独特生物学功能的工具。
• Degradation of cyclin-dependent kinase 4/6 (CDK4/6) by conjugation of CDK4/6 inhibitors with E3 ligase ligand and methods of use
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10865204B2

  公开（公告）日：2020-12-15

  The present application provides bifunctional compounds of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 4 (CDK4) and/or cyclin-dependent kinase 6 (CDK6). The present application also relates to methods for the targeted degradation of CDK4 and/or CDK6 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK4 and/or CDK6 which can be utilized in the treatment of disorders modulated by CDK4 and/or CDK6.

  本申请提供了式 (I) 的双官能化合物： 或其药学上可接受的盐、水合物、溶媒、原药、立体异构体或同系物，它们可作为细胞周期蛋白依赖性激酶 4 (CDK4) 和/或细胞周期蛋白依赖性激酶 6 (CDK6) 的蛋白质降解诱导分子。本申请还涉及通过使用双功能化合物靶向降解 CDK4 和/或 CDK6 的方法，该双功能化合物将泛素连接酶结合分子与能够与 CDK4 和/或 CDK6 结合的配体连接起来，可用于治疗受 CDK4 和/或 CDK6 调节的疾病。
• DEGRADATION OF CYCLIN-DEPENDENT KINASE 4/6 (CDK4/6) BY CONJUGATION OF CDK4/6 INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20190092768A1

  公开（公告）日：2019-03-28

  The present application provides bifunctional compounds of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 4 (CDK4) and/or cyclin-dependent kinase 6 (CDK6). The present application also relates to methods for the targeted degradation of CDK4 and/or CDK6 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK4 and/or CDK6 which can be utilized in the treatment of disorders modulated by CDK4 and/or CDK6.