N-(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)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)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-(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)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
• 英文别名: N-[2-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]ethyl]-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide
• 化学式: C₄₁H₄₄N₁₀O₈
• 分子量: 804.863
• InChiKey: LIFBUOCXOCIEST-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  59
• 可旋转键数：
  12
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  216
• 氢给体数：
  3
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  帕布昔利布 在 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 N-(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)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  参考文献：
  名称：

  细胞周期蛋白依赖性激酶 4 和 6 的双重选择性降解剂的开发。

  摘要：

  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。

  DOI：

  10.1002/anie.201901336

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 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。
• [EN] PROTEOLYSIS-TARGETING CHIMERAS<br/>[FR] CHIMÈRES CIBLANT LA PROTÉOLYSE
  申请人：WISTAR INST

  公开号：WO2020092662A1

  公开（公告）日：2020-05-07

  The present disclosure provides compounds of the formula (I) wherein these compounds contain a ligand which binds to one or more target proteins such as CDK4 or CDK6 and a ligand which binds to the machinery associated with the ubiquitinating protein machinery. Also provided herein are methods of using these compounds in compositions or methods of treating patients with these compounds for the treatment of a disease or disorders such as cancer.

  本公开提供了式（I）的化合物，这些化合物包含与CDK4或CDK6等一种或多种靶蛋白结合的配体，以及与泛素化蛋白机器相关的配体。本公开还提供了使用这些化合物在组合物中或用于治疗疾病或疾病的方法，例如癌症患者的方法。
• 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：EP3827000A1

  公开（公告）日：2021-06-02
• PROTEOLYSIS-TARGETING CHIMERAS
  申请人：The Wistar Institute of Anatomy and Biology

  公开号：US20220002291A1

  公开（公告）日：2022-01-06

  The present disclosure provides compounds of the formula (I) wherein these compounds contain a ligand which binds to one or more target proteins such as CDK4 or CDK6 and a ligand which binds to the machinery associated with the ubiquitinating protein machinery. Also provided herein are methods of using these compounds in compositions or methods of treating patients with these compounds for the treatment of a disease or disorders such as cancer.
• [EN] INK4 TUMOR SUPPRESSOR PROTEINS MEDIATE RESISTANCE TO CDK4/6 KINASE INHIBITORS<br/>[FR] PROTÉINES SUPPRESSEURS DE TUMEURS INK4 VÉHICULANT LA RÉSISTANCE À DES INHIBITEURS DE KINASE CDK4/6
  申请人：[en]MEMORIAL SLOAN-KETTERING CANCER CENTER

  公开号：WO2023039081A2

  公开（公告）日：2023-03-16

  The present disclosure relates to compounds according to Formula (I), Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, compositions including such compounds, and methods useful for treating, preventing, and/or ameliorating a CDK4 and/or CDK6-mediated disorder, disease, or condition (e.g., cancer such as breast cancer) in a subject.