2-(2-methoxyphenyl)-7-methyl-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-4(3H)-one | 1207188-38-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 2-(2-methoxyphenyl)-7-methyl-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
• 英文别名: 2-(3-methoxyphenyl)-7-methyl-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one
• CAS: 1207188-38-2
• 化学式: C₁₈H₁₈N₂O₂S
• 分子量: 326.419
• InChiKey: AGYBTGXTDBRHMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  78.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-甲基环己酮 在 盐酸 、 sulfur 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 12.0h， 生成 2-(2-methoxyphenyl)-7-methyl-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  Discovery of a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That Induces AMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer

  摘要：

  Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.

  DOI：

  10.1021/acs.jmedchem.7b00275

文献信息

• BRD4抑制剂及其在肿瘤治疗药物中的应用
  申请人：四川大学

  公开号：CN106905347B

  公开（公告）日：2019-04-16

  本发明涉及靶向BRD4的抑制剂及其在肿瘤治疗药物中的应用，属于抗肿瘤药学技术领域。本发明解决的技术问题是提供一种作为BRD4抑制剂的化合物。该化合物包括如下所示的化合物或其药学上可接受的盐。本发明的化合物或其药学上可接受的盐，可以作为BRD4抑制剂，具有较明显的抗乳腺癌治疗效果。
• Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening
  作者：Krishna P. Ravindranathan、Valsan Mandiyan、Anil R. Ekkati、Jae H. Bae、Joseph Schlessinger、William L. Jorgensen

  DOI：10.1021/jm901386e

  日期：2010.2.25

  Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed oil both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC50 values of 23 and 50 mu M. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 mu M. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.