N-(2-(2-(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)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)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: N-(2-(2-(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)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide
• 英文别名: N-[2-[2-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]acetamide
• 化学式: C₄₅H₅₃N₁₁O₉
• 分子量: 891.984
• InChiKey: JWNZXWGMBRXMPK-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 盐酸 、 potassium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 potassium iodide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 20.0h， 生成 N-(2-(2-(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)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide
  参考文献：
  名称：

  由大脑，VHL和新型IAP招募的PROTAC介导的选择性CDK6降解

  摘要：

  CDK4和CDK6抑制剂已成为FDA批准的针对乳腺癌患者的重要治疗选择。CDK4 / 6抑制剂药物的特性和药理作用已得到广泛介绍，并且还报道了通过PROTAC策略对这些靶标降解的研究。PROTAC是一类新型的小分子，与传统的抑制剂相比，可通过改变细胞泛素-蛋白酶体系统的方向来降解目标靶标蛋白，从而为药理差异化提供潜力。我们在这里报告了基于palbociclib的PROTAC的制备，其中结合了三种不同的E3连接酶（包括新型IAP粘合剂）的粘合剂，该粘合剂可有效降解细胞中的CDK4和CDK6。此外，

  DOI：

  10.1016/j.bmcl.2020.127106

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。
• 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.
• Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs
  作者：Niall A. Anderson、Jenni Cryan、Adil Ahmed、Han Dai、Grant A. McGonagle、Christine Rozier、Andrew B. Benowitz

  DOI：10.1016/j.bmcl.2020.127106

  日期：2020.5

  reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively

  CDK4和CDK6抑制剂已成为FDA批准的针对乳腺癌患者的重要治疗选择。CDK4 / 6抑制剂药物的特性和药理作用已得到广泛介绍，并且还报道了通过PROTAC策略对这些靶标降解的研究。PROTAC是一类新型的小分子，与传统的抑制剂相比，可通过改变细胞泛素-蛋白酶体系统的方向来降解目标靶标蛋白，从而为药理差异化提供潜力。我们在这里报告了基于palbociclib的PROTAC的制备，其中结合了三种不同的E3连接酶（包括新型IAP粘合剂）的粘合剂，该粘合剂可有效降解细胞中的CDK4和CDK6。此外，