Wee1抑制剂 | 622855-37-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: Wee1抑制剂
• 英文名称: 4-(2-Chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione
• 英文别名: Wee1 Inhibitor；Wee1；4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione；4-(2-chlorophenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-1,3-dione
• CAS: 622855-37-2
• 化学式: C₂₀H₁₁ClN₂O₃
• 分子量: 362.772
• InChiKey: DPEXRCOBPACFOO-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：10mg/mL，乙醇：10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  26
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  82.2
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• 储存条件：
  存储条件：2-8°C，需密封并保持干燥。

制备方法与用途

WEE1-IN-4 是一种有效的 WEE1 激酶抑制剂，其 IC50 值为 0.011 μM。

反应信息

• 作为产物：
  描述：

  5-甲氧基-1H-吲哚-2-羧酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 palladium on activated charcoal manganese(IV) oxide 、 硫酸 、 二苯基膦叠氮化物 、 氢气 、 吡啶盐酸盐 、 sodium carbonate 、 三乙胺 、 叔丁醇 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 3.0~200.0 ℃ 、413.68 kPa 条件下， 反应 32.3h， 生成 Wee1抑制剂
  参考文献：
  名称：

  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. Structure−Activity Relationships for Chromophore Modification and Phenyl Ring Substitution

  摘要：

  High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

  DOI：

  10.1021/jm0512591

文献信息

• Inhibitors of checkpoint kinases (Wee1 and Chk1)
  申请人：Pfizer Inc

  公开号：US07094798B1

  公开（公告）日：2006-08-22

  This invention relates to pyrrolocarbazole derivatives according formula I wherein R1, R2, R7, R8, R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1

  本发明涉及式I所示的吡咯喹啉衍生物，其中R1、R2、R7、R8、R9、X和Y如规范中所定义，其中所述衍生物特异性地抑制检查点激酶Wee1和Chk1中的一个或两个。
• [EN] INHIBITORS OF CHECKPOINT KINASES (WEE1 AND CHK1)<br/>[FR] INHIBITEURS DE CHECKPOINT KINASES (WEE1 ET CHK1)
  申请人：WARNER LAMBERT CO

  公开号：WO2003091255A1

  公开（公告）日：2003-11-06

  This invention relates to pyrrolocarbazole derivatives according formula (I) wherein R1, R2, r7, R8 R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1.

  本发明涉及公式（I）中的吡咯并咔唑衍生物，其中R1，R2，r7，R8，R9，X和Y如规范中所定义，其中所述衍生物特异性地抑制检查点激酶Wee1和Chk1中的一个或两个。
• PYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
  申请人：ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

  公开号：US20160122361A1

  公开（公告）日：2016-05-05

  This disclosure relates to compounds, methods for their preparation, pharmaceutical compositions including these compounds and methods for the treatment of cellular proliferative disorders, including, but not limited to, cancer.

  本公开涉及化合物、其制备方法、包括这些化合物的制药组合物以及治疗细胞增殖性疾病的方法，包括但不限于癌症。
• ANTICANCER AGENT COMPOSITION
  申请人：Carna Biosciences, Inc.

  公开号：EP3100742A1

  公开（公告）日：2016-12-07

  Provided is a pharmaceutical composition comprising a Cdc7 inhibitor and an M phase promoter. In particular, the Cdc7 inhibitor contained in the pharmaceutical composition is a furanone derivative represented by formula (I), or a pharmaceutically acceptable salt thereof. (In the formula, A is -COOR1 or a hydrogen atom; R1 is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocycle; R2 and R3 are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted phenyl group, an optionally substituted heterocycle, an optionally substituted heterocyclic condensed ring, or an optionally substituted amino group. Alternatively, R2 and R3 may, together with the nitrogen atoms bonding the same, form an optionally substituted heterocycle or optionally substituted heterocyclic condensed ring. R4 is a hydrogen atom or halogen atom. However, if A is -COOR1, R2 and R3 are not both simultaneously optionally substituted amino groups. When A is a hydrogen atom, R3 is a hydrogen atom.)

  本发明提供了一种药物组合物，其中包含一种 Cdc7 抑制剂和一种 M 期促进剂。特别是，药物组合物中所含的 Cdc7 抑制剂是由式（I）表示的呋喃酮衍生物或其药学上可接受的盐。(式中，A为-COOR1或氢原子；R1为氢原子、任选取代的烃基或任选取代的杂环；R2和R3相同或不同，各自为氢原子、任选取代的烃基、任选取代的苯基、任选取代的杂环、任选取代的杂环缩合环或任选取代的氨基。或者，R2 和 R3 可与结合在一起的氮原子一起形成任选取代的杂环或任选取代的杂环缩合环。R4 是氢原子或卤素原子。但是，如果 A 是-COOR1，R2 和 R3 不能同时是任选取代的氨基。当 A 为氢原子时，R3 为氢原子）。
• PROGNOSTIC BIOMARKER FOR CANCER
  申请人：Universitat Autònoma de Barcelona

  公开号：EP3231875A1

  公开（公告）日：2017-10-18

  The invention relates to an in vitro method for determining the prognosis of a patient suffering from cancer, wherein the cancer is not hepatocarcinoma, based on CDK5RAP3 gene expression levels. The invention also relates to in vitro methods for predicting the clinical response of a patient suffering from cancer to a treatment with a DNA damaging agent, or for selecting a patient suffering from cancer for a therapy with a DNA damaging agent or for selecting a therapy for a patient suffering from cancer.

  本发明涉及一种根据CDK5RAP3基因表达水平确定癌症患者预后的体外方法，其中癌症不是肝癌。本发明还涉及一种体外方法，用于预测癌症患者对 DNA 损伤剂治疗的临床反应，或用于选择癌症患者接受 DNA 损伤剂治疗，或用于选择癌症患者的治疗方法。