4-[(2Z)-2-(2-amino-5-methyl-4-oxocyclohexa-2,5-dien-1-ylidene)hydrazinyl]-N-pyridin-2-ylbenzenesulfonamide | 1395084-25-9

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 偶氮苯
• 英文名称: 4-[(2Z)-2-(2-amino-5-methyl-4-oxocyclohexa-2,5-dien-1-ylidene)hydrazinyl]-N-pyridin-2-ylbenzenesulfonamide
• 英文别名: (E)-4-((2-amino-4-hydroxy-5-methylphenyl)diazenyl)-N-(pyridin-2-yl)benzenesulfonamide；4-[(1E)-2-(2-amino-4-hydroxy-5-methylphenyl)diazenyl]-N-2-pyridinylbenzenesulfonamide；MS 436；MS436
• CAS: 1395084-25-9
• 化学式: C₁₈H₁₇N₅O₃S
• 分子量: 383.431
• InChiKey: DZTGIRNXWSZBIM-QURGRASLSA-N

物化性质

• 沸点：
  673.7±65.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)
• 溶解度：
  不溶于水；不溶于乙醇； ≥19.15 mg/mL，溶于 DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  3.89
• 重原子数：
  27.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  130.03
• 氢给体数：
  3.0
• 氢受体数：
  7.0

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2～8℃

制备方法与用途

生物活性

MS436 是一种溴结构域抑制剂，有效作用于 BRD4 的 BrD1 结构域，Ki 值为 30-50 nM，并且相比对 BrD2 选择性高 10 倍。

靶点

• Ki: 30-50 nM (BRD4 溴结构域)

体外研究

MS436 通过一系列水介导的相互作用，显示出低纳摩尔亲和力（估计 Ki 值为 30-50 nM），优先与第一个溴结构域结合而非第二个。MS436 能够有效抑制小鼠巨噬细胞中 NF-κB 引导的一氧化氮 (NO) 和促炎细胞因子白介素-6 (IL-6) 的产生，代表了一类新的溴结构域抑制剂，并将促进对 BRD4 两个溴结构域在基因表达中的生物学功能的进一步研究。MS436 对 BRD4 BrD1 的亲和力估计为 Ki = 30-50 nM，而对 BrD2 的选择性高 10 倍，这种独特的选择性是通过一系列水介导的分子相互作用实现的。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  磺胺吡啶	sulphapyridine	144-83-2	C11H11N3O2S	249.293
  N-[4-[(吡啶-2-基氨基)磺酰基]苯基]-乙酰胺	N-acetylsulfapyridine	19077-98-6	C13H13N3O3S	291.331
  N-硝基-N-吡啶-2-基苯磺酰胺	4-nitro-N-(pyridin-2-yl)benzenesulfonamide	1028-11-1	C11H9N3O4S	279.276

反应信息

• 作为产物：
  描述：

  N-硝基-N-吡啶-2-基苯磺酰胺 在 盐酸 、 铁粉 、 氯化铵 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 4.25h， 生成 4-[(2Z)-2-(2-amino-5-methyl-4-oxocyclohexa-2,5-dien-1-ylidene)hydrazinyl]-N-pyridin-2-ylbenzenesulfonamide
  参考文献：
  名称：

  Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains

  摘要：

  BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.

  DOI：

  10.1021/jm401334s

文献信息

• [EN] INHIBITORS OF BROMODOMAINS AS MODULATORS OF GENE EXPRESSION<br/>[FR] INHIBITEURS DE BROMODOMAINES COMME MODULATEURS D'EXPRESSION GÉNIQUE
  申请人：ZHOU MING-MING

  公开号：WO2012116170A1

  公开（公告）日：2012-08-30

  This disclosure relates generally to compounds and compositions comprising one or more diphenylethylene, diphenylethylyne, and azobenzene analogs. These compounds are useful for treating diseases associated with NF-kB and p53 activity, such as cancer and inflammatory disease.

  这份披露通常涉及包含一种或多种二苯乙烯、二苯乙炔和偶氮苯类似物的化合物和组合物。这些化合物对治疗与NF-kB和p53活性相关的疾病，如癌症和炎症性疾病，具有用处。
• [EN] SUBSTITUTED BENZOTHIOPHENE ANALOGS AS SELECTIVE ESTROGEN RECEPTOR DEGRADERS<br/>[FR] ANALOGUES DE BENZOTHIOPHÈNE SUBSTITUÉS EN TANT QU'AGENTS DE DÉGRADATION SÉLECTIFS DU RÉCEPTEUR D'ŒSTROGÈNES
  申请人：UNIV ILLINOIS

  公开号：WO2019157020A1

  公开（公告）日：2019-08-15

  In one aspect, the disclosure relates to relates to substituted benzothiophene analogs which are useful as selective degraders of estrogen receptor, methods of making same, pharmaceutical compositions comprising same, and methods of treating one or more clinical conditions associated with estrogen receptor, such as a cancer, including breast cancer, or osteoporosis. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

  在一个方面，该披露涉及与取代苯并噻吩类似物相关的内容，这些类似物可用作雌激素受体的选择性降解剂，制备方法，包含它们的药物组合物，以及治疗与雌激素受体相关的一个或多个临床病况的方法，如癌症，包括乳腺癌，或骨质疏松症。此摘要旨在用作在特定领域进行搜索的扫描工具，并不意在限制本披露。
• [EN] HETERO-BIFUNCTIONAL DEGRADER COMPOUNDS AND THEIR USE AS MODULATORS OF TARGETED UBIQUINATION (VHL)<br/>[FR] COMPOSÉS DE DÉGRADATION HÉTÉRO-BIFONCTIONNELS ET LEUR UTILISATION EN TANT QUE MODULATEURS DE L'UBIQUINATION CIBLÉE (VHL)
  申请人：GENENTECH INC

  公开号：WO2019183523A1

  公开（公告）日：2019-09-26

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds that contain on one end a VHL ligand moiety, which binds to the VHL ubiquitin ligase (E3), and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. The target protein may be EGFR. Also disclosed are VHL ligands.

  本公开涉及双功能化合物，可用作靶向泛素化的调节剂。特别是，本公开是针对包含在一端具有VHL配体基团的化合物，该基团结合到VHL泛素连接酶(E3)，而在另一端具有结合目标蛋白的基团，从而实现目标蛋白/多肽的降解。目标蛋白可以是EGFR。还公开了VHL配体。
• INHIBITORS OF BROMODOMAINS AS MODULATORS OF GENE EXPRESSION
  申请人：Zhou Ming-Ming

  公开号：US20140066410A1

  公开（公告）日：2014-03-06

  This disclosure relates generally to compounds and compositions comprising one or more diphenylethylene, diphenylethylyne, and azobenzene analogs. These compounds are useful for treating diseases associated with NF-kB and p53 activity, such as cancer and inflammatory disease.

  本公开涉及一种化合物和组合物，其中包括一种或多种二苯乙烯，二苯乙炔和偶氮苯类似物。这些化合物可用于治疗与NF-kB和p53活性相关的疾病，如癌症和炎症性疾病。
• Combinations of LSD1 inhibitors for use in the treatment of solid tumors
  申请人：ORYZON GENOMICS, S.A.

  公开号：US10265279B2

  公开（公告）日：2019-04-23

  The instant invention relates to therapeutic combinations of LSD1 inhibitors and one or more other active pharmaceutical ingredient(s) or pharmaceutically acceptable salts thereof. The combinations are particularly useful for treating neoplastic diseases, such as cancer, particularly small cell lung cancer (SCLC).

  本发明涉及 LSD1 抑制剂和一种或多种其他活性药物成分或其药学上可接受的盐的治疗组合。这些组合物特别适用于治疗肿瘤性疾病，如癌症，尤其是小细胞肺癌（SCLC）。