methyl 2-chloro-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylate | 1425933-43-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl 2-chloro-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylate
• 英文别名: methyl 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-4-carboxylate；methyl 2-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidine-4-carboxylate
• CAS: 1425933-43-2
• 化学式: C₁₂H₁₂ClN₅O₂
• 分子量: 293.713
• InChiKey: ZAQWZMAKNOCUQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  92.8
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-chloro-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylate 在 水 、 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 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.66h， 生成 3-[[4-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-6-(prop-2-ynylcarbamoyl)pyrimidin-2-yl]piperazin-1-yl]methyl]benzenesulfonyl fluoride
  参考文献：
  名称：

  Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes

  摘要：

  Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while; avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, highlighting the utility of lysine-targeted sulfonyl fluoride probes in demanding chemoproteomic applications.

  DOI：

  10.1021/jacs.6b08536
• 作为产物：
  描述：

  2-氯嘧啶-4-甲酸甲酯 、 3-氨基-5-环丙基-1H-吡唑 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以57%的产率得到methyl 2-chloro-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylate
  参考文献：
  名称：

  Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes

  摘要：

  Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while; avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, highlighting the utility of lysine-targeted sulfonyl fluoride probes in demanding chemoproteomic applications.

  DOI：

  10.1021/jacs.6b08536

文献信息

• [EN] SERINE/THREONINE PAK1 INHIBITORS<br/>[FR] INHIBITEURS DE SÉRINE/THRÉONINE PAK1
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013026914A1

  公开（公告）日：2013-02-28

  Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有以下式I的化合物，其中A、Z、R1a、R1b、R2、R3、R4、R5、R6、R7、R9、R10、Ra、Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了用于治疗癌症和高增殖性疾病的组合物和方法。
• [EN] MULTIKINASE DEGRADERS<br/>[FR] AGENTS DE DÉGRADATION MULTIKINASES
  申请人：UNIV HOUSTON SYSTEM

  公开号：WO2021021797A1

  公开（公告）日：2021-02-04

  Multikinase degraders described herein contain on one end a Von Hippel-Lindau (VHL) E3 ligase ligand or cereblon E3 ligase recruiter moiety, which bind to the VHL or cereblon E3 ubiquitin ligase (defined as a ubiquitin ligand binding moiety or ULM group), respectively, and on the other end a promiscuous kinase ligand that binds a target protein kinase (defined as a protein/polypeptide targeting moiety or PTM group), such that the target protein is in close proximity to the ubiquitin ligase. This leads to the ubiquitination and subsequent degradation (and inhibition) of the target protein. Specific present multikinase degraders as shown bind about 360 out of 400 tested kinases, showing that they are much more general kinase binders and degraders than any previously reported.

  本文描述的多激酶降解剂在一端含有 Von Hippel-Lindau（VHL）E3连接酶配体或 cereblon E3连接酶招募子，它们分别结合到 VHL 或 cereblon E3泛素连接酶（定义为泛素连接配体结合基团或ULM组），另一端含有结合靶蛋白激酶的多面手激酶配体（定义为蛋白/多肽靶向基团或PTM组），使得靶蛋白与泛素连接酶处于近距离。这导致靶蛋白的泛素化和随后的降解（和抑制）。特定的当前多激酶降解剂如所示结合了约400个被测试激酶中的约360个，表明它们比以往任何报道的激酶结合剂和降解剂都更广泛。
• [EN] MODULATORS OF MYC FAMILY PROTO-ONCOGENE PROTEIN<br/>[FR] MODULATEURS DE LA PROTÉINE PROTO-ONCOGÈNE DE LA FAMILLE MYC
  申请人：NALO THERAPEUTICS

  公开号：WO2022046861A1

  公开（公告）日：2022-03-03

  Disclosed herein are compounds and compositions having potency in the modulation of Myc family proteins. Such compounds and compositions can be used in the treatment of proliferative diseases, such as cancer, or in the treatment of disease where modulation of Myc family proteins is desired. Also disclosed herein are methods of using said compounds and compositions.

  本文中披露了具有调节Myc家族蛋白活性的药物和配方。这些药物和配方可用于治疗增生性疾病，如癌症，或治疗需要调节Myc家族蛋白的疾病。本文还披露了使用上述药物和配方的方法。
• SERINE/THREONINE KINASE INHIBITORS
  申请人：Aliagas-Martin Ignacio

  公开号：US20130225620A1

  公开（公告）日：2013-08-29

  Compounds having the formula I wherein A, Z, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R a , R b and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有公式I的化合物，其中A，Z，R1a，R1b，R2，R3，R4，R5，R6，R7，R9，R10，Ra，Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了治疗癌症和高增殖性疾病的组合物和方法。
• Serine/threonine kinase inhibitors
  申请人：Aliagas-Martin Ignacio

  公开号：US08637537B2

  公开（公告）日：2014-01-28

  Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有式I的化合物，其中A，Z，R1a，R1b，R2，R3，R4，R5，R6，R7，R9，R10，Ra，Rb和n如本文所定义，是PAK1的抑制剂。还公开了用于治疗癌症和增殖性疾病的组合物和方法。