4-(2,3-dichlorobenzoyl)-N-[2-[[4-(2,3-dichlorobenzoyl)-1-methylpyrrole-2-carbonyl]amino]ethyl]-1-methylpyrrole-2-carboxamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(2,3-dichlorobenzoyl)-N-[2-[[4-(2,3-dichlorobenzoyl)-1-methylpyrrole-2-carbonyl]amino]ethyl]-1-methylpyrrole-2-carboxamide
• 英文别名: 4-[2,3-Bis(Chloranyl)phenyl]carbonyl-N-[2-[[4-[2,3-Bis(Chloranyl)phenyl]carbonyl-1-Methyl-Pyrrol-2-Yl]carbonylamino]ethyl]-1-Methyl-Pyrrole-2-Carboxamide
• 化学式: C₂₈H₂₂Cl₄N₄O₄
• 分子量: 620.319
• InChiKey: JORSMLRHZLRFBN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  二氯苯甲酰氯 在 aluminum (III) chloride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 4-(2,3-dichlorobenzoyl)-N-[2-[[4-(2,3-dichlorobenzoyl)-1-methylpyrrole-2-carbonyl]amino]ethyl]-1-methylpyrrole-2-carboxamide
  参考文献：
  名称：

  Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator

  摘要：

  Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.05.004

文献信息

• PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER
  申请人：TOLERO PHARMACEUTICALS, INC.

  公开号：US20200237766A1

  公开（公告）日：2020-07-30

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• [EN] PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER<br/>[FR] ACTIVATEURS DE PKM2 EN COMBINAISON AVEC DES ESPÈCES RÉACTIVES DE L'OXYGÈNE POUR LE TRAITEMENT DU CANCER
  申请人：TOLERO PHARMACEUTICALS INC

  公开号：WO2019075367A1

  公开（公告）日：2019-04-18

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator
  作者：Yumi Matsui、Isao Yasumatsu、Takashi Asahi、Takahiro Kitamura、Kazuo Kanai、Osamu Ubukata、Hitoshi Hayasaka、Sachiko Takaishi、Hiroyuki Hanzawa、Shinichi Katakura

  DOI：10.1016/j.bmc.2017.05.004

  日期：2017.7

  Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators. (C) 2017 Elsevier Ltd. All rights reserved.