罗米地辛 | 128517-07-7

• 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 - 有机酸及其衍生物 - 肽模拟物
• 中文名称: 罗米地辛
• 中文别名: FK228罗米地辛
• 英文名称: (1S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
• CAS: 128517-07-7
• 化学式: C₂₄H₃₆N₄O₆S₂
• 分子量: 540.7
• InChiKey: OHRURASPPZQGQM-WDCUYUQDSA-N

物化性质

• 熔点：
  219-224°C
• 沸点：
  942.8±65.0 °C(Predicted)
• 密度：
  1.174
• 溶解度：
  溶于DMSO（高达10mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  36
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

毒理性

• 肝毒性

在 romidepsin 治疗皮肤 T 细胞淋巴瘤 (CTLC) 和外围 T 细胞淋巴瘤 (PTLC) 的临床试验中，治疗期间血清酶水平升高的发生率在 7% 到 20% 之间，但这些异常通常是短暂的、轻微的，并不需要调整剂量。血清 ALT 升高超过 5 倍正常上限 (ULN) 的患者占 6%。在 romidepsin 的上市前临床试验中，接受治疗的患者中没有肝炎、黄疸或临床明显的肝脏损伤的报告。Romidepsin 在临床上使用有限，但没有证据表明它与显著的肝脏损伤有关。 Romidepsin 还具有免疫调节活性，并据报道可以引起潜伏 DNA 病毒的再激活，包括Epstein-Barr 病毒、水痘带状疱疹病毒和乙型肝炎病毒。乙型肝炎再激活发生在一名最初 HBsAg 阴性但抗-HBc 和抗-HBs 反应性的患者中。尽管如此，乙型肝炎再激活的临床特征是轻微的，并且对口服抗病毒治疗有反应。在 EB 病毒相关淋巴瘤患者中，romidepsin 与 EB 病毒感染的严重再激活和急性肝炎有关，这种肝炎可能很严重，甚至可能是致命的。 可能性评分：C（可能是临床明显肝脏损伤的原因，可能是由乙型肝炎或 EB 病毒感染的再激活引起的）。

In clinical trials of romidepsin in patients with CTLC and PTLC, the rates of serum enzyme elevations during therapy ranged from 7% to 20%, but the abnormalities were usually transient and mild and did not require dose modifications. Serum ALT elevations above 5 times ULN occurred in 6% of patients. In the preregistration clinical trials of romidepsin, there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Romidepsin has had limited clinical use, but there is no evidence that it is associated with significant liver injury. Romidepsin also has immunomodulatory activities and has been reported to cause reactivation of latent DNA viruses including Epstein-Barr, varicella zoster and hepatitis B virus. Reactivation of hepatitis B occurred in a patient who was initially negative for HBsAg, but reactive for anti-HBc and anti-HBs. Nevertheless, the clinical features of hepatitis B reactivation were mild and responded to oral antiviral therapy. In patients with EBV associated lymphoma, romidepsin has been associated with severe reactivation of EBV infection and acute hepatitis that can be severe and even fatal. Likelihood score: C (probable cause of clinically apparent liver injury, which can be due to reactivation of hepatitis B or EBV infection).

来源:LiverTox

安全信息

• 海关编码：
  29349990
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

罗米地辛简介

罗米地辛是从革兰氏阴性细菌中分离出的一种组蛋白去乙酰化酶抑制剂（HDACi），也被称为968号青紫色杆菌。目前，罗米地辛在临床领域主要用于治疗外周T细胞淋巴瘤，并且是应用最成功和使用最广泛的药物之一。然而，在包括肝细胞癌（HCC）在内的实体肿瘤中的应用仍在研究阶段。

生物活性

罗米地辛 (FK228, Depsipeptide, FR 901228, NSC 630176) 是一种有效的HDAC1和HDAC2抑制剂，其无细胞试验中IC50分别为36 nM和47 nM。在神经母细胞瘤肿瘤细胞中，罗米地辛可以控制生长并诱导凋亡。

靶点

• HDAC1 (Cell-free assay): 36 nM
• HDAC2 (Cell-free assay): 47 nM

体外研究

罗米地辛能够抑制非小细胞肺癌（NSCLC）细胞系的生长，IC50范围从1.3 ng/mL到4.9 ng/mL。此外，罗米地辛还能降低厄洛替尼对NSCLC细胞系的抑制浓度，从而增加其对厄洛替尼的敏感性。处理72小时后，罗米地辛可以显著抑制6/6 人神经母细胞瘤（NB）肿瘤细胞系的生长，而 NIH3T3细胞系则未受影响。

罗米地辛表现出选择性的细胞毒性作用，不仅针对单拷贝或N-myc多拷贝的NB细胞系，还对含有正常或突变p53以及携带ALK突变体的细胞系具有剂量依赖性的影响。

体内研究

与PBS对照组相比，单独使用厄洛替尼和罗米地辛分别可以抑制NCI-H1299细胞系异种移植生长72%和43%，但无显著统计学意义。只有当两种药物联用时，才能对肿瘤生长产生明显抑制作用，此时生长被抑制到约28%。在免疫功能低下的小鼠中，罗米地辛能够剂量依赖性地抑制皮下NB异种移植的生长。此外，在NB病人的肿瘤组织中，罗米地辛可诱导某些基因的表达，如p21、p75和NTRK (TrkA)。

文献信息

• Combination methods of treating cancer
  申请人：Bacopoulos G. Nicholas

  公开号：US20070190022A1

  公开（公告）日：2007-08-16

  The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first treatment procedure, and a second amount of an anti-cancer agent in a second treatment procedure. The first and second amounts together comprise a therapeutically effective amount. The effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.

  本发明涉及一种治疗癌症的方法，通过在第一次治疗过程中向需要治疗的对象给予一定量的组蛋白去乙酰化酶（HDAC）抑制剂或其药学上可接受的盐或水合物，以及在第二次治疗过程中给予一定量的抗癌剂。第一次和第二次给予的药量加起来构成治疗上有效的药量。HDAC抑制剂和抗癌剂的作用可能是加成或协同的。
• COMBINATION METHODS OF TREATING CANCER
  申请人：Bacopoulos Nicholas G.

  公开号：US20100273732A1

  公开（公告）日：2010-10-28

  The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first treatment procedure, and a second amount of an anti-cancer agent in a second treatment procedure. The first and second amounts together comprise a therapeutically effective amount. The effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.

  本发明涉及一种治疗需要治疗的主体癌症的方法，包括在第一治疗程序中向需要治疗的主体中给予一定量的组蛋白去乙酰化酶（HDAC）抑制剂或其药学上可接受的盐或水合物，以及在第二治疗程序中给予一定量的抗癌药物。第一和第二剂量共同组成治疗有效量。HDAC抑制剂和抗癌药物的作用可能是相加或协同的。
• FLOUROUS METABOLICALLY STABLE PEPTIDE ANALOGS
  申请人：Université de Strasbourg

  公开号：EP3257863A1

  公开（公告）日：2017-12-20

  The present invention relates to metabolically stable and non-immunogen analogs completely hydrosoluble at physiological pH, and their use for the prevention or treatment of diseases mediated by G-protein coupled receptor (GPCR), in particular (Central Nervous System) CNS and cardiovascular diseases or disorders.

  本发明涉及在生理 pH 值下完全水溶的代谢稳定的非免疫原类似物，以及它们在预防或治疗由 G 蛋白偶联受体（GPCR）介导的疾病，特别是（中枢神经系统）中枢神经系统和心血管疾病或紊乱方面的用途。
• Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance
  申请人：CHILDREN'S MEDICAL CENTER CORPORATION

  公开号：US10669528B2

  公开（公告）日：2020-06-02

  The methods and compositions described herein relate to producing, expanding, enriching, and/or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGFβ signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation. In some embodiments, the technology described herein relates to transplantation of hematopoietic stem cells.

  本文所述的方法和组合物涉及用一种或多种药剂处理体内外造血干细胞，以产生、扩增、富集和/或维持造血干细胞，这些药剂具有两种或多种活性，选自组蛋白甲基化调节；TGFβ信号转导抑制；p38信号转导抑制；典型Wnt信号转导激活；组蛋白乙酰化调节。在某些实施方案中，本文所述技术涉及造血干细胞的移植。
• Substituted pyridines as inhibitors of DNMT1
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US10975056B2

  公开（公告）日：2021-04-13

  The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代的吡啶衍生物。具体地说，本发明是针对符合式（Iar）的化合物： 其中 Yar、X1ar、X2ar、R1ar、R2ar、R3ar、R4ar 和 R5ar 如本文所定义；或其药学上可接受的盐或原药。 本发明的化合物是 DNMT1 的选择性抑制剂，可用于治疗癌症、癌前综合征、β 血红蛋白病疾病、镰状细胞病、镰状细胞性贫血和β 地中海贫血以及与 DNMT1 抑制相关的疾病。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步涉及使用本发明化合物或包含本发明化合物的药物组合物抑制 DNMT1 活性和治疗与之相关疾病的方法。