4-acetyl-5-(4-bromo-phenyl)-3-hydroxy-1-[2-(4-morpholin-4-ylphenyl)-ethyl]-1,5-dihydro-pyrrol-2-one | 1235711-32-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 4-acetyl-5-(4-bromo-phenyl)-3-hydroxy-1-[2-(4-morpholin-4-ylphenyl)-ethyl]-1,5-dihydro-pyrrol-2-one
• 英文别名: 3-acetyl-2-(4-bromophenyl)-4-hydroxy-1-[2-(4-morpholin-4-ylphenyl)ethyl]-2H-pyrrol-5-one
• CAS: 1235711-32-6
• 化学式: C₂₄H₂₅BrN₂O₄
• 分子量: 485.377
• InChiKey: DMEIABZHZNODRA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  5

文献信息

• Novel specific inhibitors of ubiquitin specific protease 7, the pharmaceutical compositions thereof and their therapeutic applications
  申请人：Hybrigenics S.A.

  公开号：EP2208725A1

  公开（公告）日：2010-07-21

  The present invention concerns new compounds of formula (I), their process of preparation and their therapeutic use.

  本发明涉及公式（I）的新化合物，它们的制备过程及其治疗用途。
• USE OF USP7 INHIBITORS FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (AML)
  申请人：Institut National de la Santé et de la Recherche Médicale (INSERM)

  公开号：EP3923987A1

  公开（公告）日：2021-12-22
• [EN] NOVEL SPECIFIC INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 7, THE PHARMACEUTICAL COMPOSITIONS THEREOF AND THEIR THERAPEUTIC APPLICATIONS<br/>[FR] NOUVEAUX INHIBITEURS SPÉCIFIQUES DE LA PROTÉASE 7 SPÉCIFIQUE DE L'UBIQUITINE, LES COMPOSITIONS PHARMACEUTIQUES DE CEUX-CI ET LEURS APPLICATIONS THÉRAPEUTIQUES
  申请人：HYBRIGENICS SA

  公开号：WO2010081783A1

  公开（公告）日：2010-07-22

  The present invention concerns new compounds of formula (I), their process of preparation and their therapeutic use.
• [EN] USE OF USP7 INHIBITORS FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (AML)<br/>[FR] UTILISATION D'INHIBITEURS DE L'USP7 POUR LE TRAITEMENT DE LA LEUCÉMIE AIGUË MYÉLOÏDE (LAM)
  申请人：INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECH MÉDICALE)

  公开号：WO2020165315A1

  公开（公告）日：2020-08-20

  Resistance of acute myeloid leukemia (AML) cells to DNA damaging therapeutic agents is dependent on CHK1 protein levels. Here, the inventors demonstrate that in AML, CHK1 protein stability relies on the expression and activity of Ubiquitin Specific Protease 7 (USP7). CHK1 and USP7 levels are positively correlated in AML cell lines and primary patient specimens with high CHK1 protein levels. USP7 associates with CHK1, leading to its stabilization by deubiquitinylation, and this association is enhanced in response to cytarabine treatment. Pharmacological or RNA interference-mediated inhibition of USP7 significantly reduced AML proliferation in vitro and in vivo, and increased AML cell death. It is important to note that USP7 inhibition synergized with cytarabine to kill AML cell lines. This is also the case in primary patient specimens with high CHK1 levels. Transcriptomic dataset analyses revealed that a USP7 gene signature is highly enriched in cells from AML patients at relapse, as well as in residual blasts from Patient Derived Xenograft (PDX) models treated with clinically relevant doses of cytarabine, strongly suggesting a relationship between USP7 expression and resistance to therapy. Finally, single cell analysis from AML patient at relapse versus diagnosis showed that a gene signature of the pre-existing subpopulation responsible for relapse is enriched in transcriptomes of patients with high USP7 level. Altogether, these data demonstrate that USP7 is a master regulator of CHK1 protein kinase in AML cells, and represents both a marker of resistance to chemotherapeutic treatments, as well as a potential therapeutic target to overcome treatment resistance.