1-[2-chloro-2-(4-fluorophenyl)ethyl]-N-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | 1234293-70-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 1-[2-chloro-2-(4-fluorophenyl)ethyl]-N-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: SI178；1-[2-chloro-2-(4-fluorophenyl)ethyl]-N-(3-fluorophenyl)pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1234293-70-9
• 化学式: C₁₉H₁₄ClF₂N₅
• 分子量: 385.803
• InChiKey: AAMZEJILAVQVEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氟苯胺 、 4-chloro-1-(2-chloro-2-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine 以 乙醇 为溶剂， 反应 3.0h， 以67%的产率得到1-[2-chloro-2-(4-fluorophenyl)ethyl]-N-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms

  摘要：

  The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.04.024

文献信息

• Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms
  作者：Emmanuele Crespan、Marco Radi、Samantha Zanoli、Silvia Schenone、Maurizio Botta、Giovanni Maga

  DOI：10.1016/j.bmc.2010.04.024

  日期：2010.6.1

  The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I. (C) 2010 Elsevier Ltd. All rights reserved.
• A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant
  作者：Marco Radi、Ralf Schneider、Anna Lucia Fallacara、Lorenzo Botta、Emmanuele Crespan、Cristina Tintori、Giovanni Maga、Miroslava Kissova、Alessia Calgani、André Richters、Franesca Musumeci、Daniel Rauh、Silvia Schenone

  DOI：10.1016/j.bmcl.2016.06.051

  日期：2016.8

  The major clinical challenge in drug-resistant chronic myelogenous leukemia (CML) is currently represented by the Bcr-Abl T315I mutant, which is unresponsive to treatment with common first and second generation ATP-competitive tyrosine kinase inhibitors (TKIs). Allosteric inhibition of Bcr-Abl represent a new frontier in the fight against resistant leukemia and few candidates have been identified in the last few years. Among these, myristate pocket (MP) binders discovered by Novartis (e.g. GNF2/5) showed promising results, although they proved to be active against the T315I mutant only in combination with first and second generation ATP-competitive inhibitors. Here we used a cascade screening approach based on sequential fluorescence polarization (FP) screening, in silico docking/dynamics studies and kinetic-enzymatic studies to identify novel MP binders. A pyrazolo[3,4-d]pyrimidine derivative (6) has been identified as a promising allosteric inhibitor active on 32D leukemia cell lines (expressing Bcr-Abl WT and T315I) with no need of combination with any ATP-competitive inhibitor. (C) 2016 Elsevier Ltd. All rights reserved.