(4-(双(4-氯苯基)甲基)哌嗪-1-基)(5-甲基-4-硝基异恶唑-3-基)甲酮 | 1360705-96-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (4-(双(4-氯苯基)甲基)哌嗪-1-基)(5-甲基-4-硝基异恶唑-3-基)甲酮
• 中文别名: [4-[双(4-氯苯基)甲基]-1-哌嗪基](5-甲基-4-硝基-3-异恶唑基)甲酮
• 英文名称: ML210
• 英文别名: [4-[Bis(4-chlorophenyl)methyl]piperazin-1-yl]-(5-methyl-4-nitro-1,2-oxazol-3-yl)methanone
• CAS: 1360705-96-9
• 化学式: C₂₂H₂₀Cl₂N₄O₄
• 分子量: 475.331
• InChiKey: VIBHJPDPEVVDTB-UHFFFAOYSA-N

物化性质

• 沸点：
  644.7±55.0 °C(Predicted)
• 密度：
  1.415±0.06 g/cm3(Predicted)
• 溶解度：
  溶于 DMSO（高达 30 mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  95.4
• 氢给体数：
  0
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

ML-210（CID 49766530）是一种选择性的谷胱甘肽过氧化物酶4（GPX4）共价抑制剂，其EC50值为0.04 μM，能够诱导铁死亡。ML-210可以有选择性地杀死表达突变型RAS的细胞，并表现出抗癌活性。

靶点	值
RAS
GPX4	(离体测定)

体外研究

ML-210在821种癌细胞系（WM88, LOX-IMVI, CJM, U257, CAKI2, A498, HT1080, MC38, PANC02）中表现出细胞杀伤活性。作为一种前药，ML-210需要在细胞内活化后与GPX4结合。对于BJeLR（HRAS V12）、BJeH-LT（无HRAS V12）和DRD细胞系，其IC50分别为71 nM、272 nM和107 nM。

反应信息

• 作为反应物：
  描述：

  (4-(双(4-氯苯基)甲基)哌嗪-1-基)(5-甲基-4-硝基异恶唑-3-基)甲酮 在 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.0h， 以61%的产率得到
  参考文献：
  名称：

  GPX4抑制剂弹头的构效关系。

  摘要：

  GPX4 的直接抑制需要活性位点硒代半胱氨酸的共价修饰。虽然表型筛选表明活化的烷基氯化物和掩蔽的腈氧化物可以共价抑制 GPX4，但缺乏对具有抑制细胞 GPX4 能力的潜在亲电弹头的系统评估。在这里，我们在几个不同的 GPX4 靶向支架上调查了超过 25 个亲电子弹头。我们发现，尽管硒代半胱氨酸残基具有预期的亲核性，但与氯乙酰胺相比，反应性减弱的亲电试剂无法抑制 GPX4。然而，我们在本研究中发现的高反应性丙炔酰胺可以替代 GPX4 抑制剂中的氯乙酰胺和硝基异恶唑弹头。我们的观察表明，亲电掩蔽策略，

  DOI：

  10.1016/j.bmcl.2020.127538
• 作为产物：
  描述：

  4,4'-二氯二苯甲酮 在 sodium tetrahydroborate 、 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 2.5h， 生成 (4-(双(4-氯苯基)甲基)哌嗪-1-基)(5-甲基-4-硝基异恶唑-3-基)甲酮
  参考文献：
  名称：

  Development of small-molecule probes that selectively kill cells induced to express mutant RAS

  摘要：

  Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.047

文献信息

• METHODS OF CANCER TREATMENT
  申请人：Ferro Therapeutics, Inc.

  公开号：US20200138829A1

  公开（公告）日：2020-05-07

  The present disclosure relates to a method of treating a subject with cancer with a ferroptosis inducer, including use of the ferroptosis inducer in combination with a second therapeutic agent.
• SYNERGISTIC DRUG COMBINATIONS PREDICTED FROM GENOMIC FEATURES AND SINGLE-AGENT RESPONSE PROFILES
  申请人：THE BROAD INSTITUTE, INC.

  公开号：US20210069230A1

  公开（公告）日：2021-03-11

  The present disclosure relates to discovery of specific synergistic drug combinations and mechanisms of drug resistance. Compositions involving newly-identified drug combinations as well as diagnostic and therapeutic methods related to such discoveries are provided.
• DECREASING IMMUNE ACTIVITY THROUGH MODULATION OF POSTCELLULAR SIGNALING FACTORS
  申请人：FLAGSHIP PIONEERING INNOVATIONS V, INC.

  公开号：US20210283091A1

  公开（公告）日：2021-09-16

  The invention provides methods of decreasing immune response by inhibiting iron-dependent cellular disassembly. The decrease in immune response may be used, for example, for treatment of a disorder associated with iron-dependent cellular disassembly, including an autoimmune disorder, allergy, or an inflammatory disorder. The invention also provides screening assays for identification of compounds that inhibit iron-dependent cellular disassembly and are also immunoinhibitory agents.
• INCREASING IMMUNE ACTIVITY THROUGH MODULATION OF POSTCELLULAR SIGNALING FACTORS
  申请人：FLAGSHIP PIONEERING INNOVATIONS V, INC.

  公开号：US20210251994A1

  公开（公告）日：2021-08-19

  The invention provides methods of increasing immune response by inducing iron-dependent cellular disassembly. The increase in immune response may be used, for example, for treatment of infection or cancer. The invention also provides screening assays for identification of compounds that induce iron-dependent cellular disassembly and are also immunostimulatory agents. The invention further provides methods for identifying immunostimulatory agents produced by cells undergoing iron-dependent cellular disassembly.
• [EN] COMBINATION ANTI-CANCER THERAPIES WITH INDUCERS OF IRON-DEPENDENT CELLULAR DISASSEMBLY<br/>[FR] POLYTHÉRAPIES ANTICANCÉREUSES AYANT DES INDUCTEURS DE DÉSASSEMBLAGE CELLULAIRE DÉPENDANT DU FER
  申请人：FLAGSHIP PIONEERING INNOVATIONS V INC

  公开号：WO2021127217A1

  公开（公告）日：2021-06-24

  The invention provides methods of treating a cancer in a subject, comprising administering to the subject a combination of (a) an anti-neoplastic agent and (b) an agent that induces iron-dependent cellular disassembly, thereby treating the cancer in the subject. In some embodiments, the cancer is resistant to the anti-neoplastic agent.