YM-254890

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: YM-254890
• 英文别名: (2S,3R)-2-acetamido-3-hydroxy-4-methylpentanoate；[(1R)-1-[(3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-[(1R)-1-methoxyethyl]-4,9,10,12,16,22-hexamethyl-15-methylidene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentazacyclodocos-6-yl]-2-methylpropyl] (2S,3R)-2-acetamido-3-hydroxy-4-methylpentanoate
• 化学式: C₄₆H₆₉N₇O₁₅
• 分子量: 960.092
• InChiKey: QVYLWCAYZGFGNF-WBWCVGBTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  68
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  286
• 氢给体数：
  5
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  YM-254890 在 超重氢 作用下， 生成 [³H]PSB-16254-YM
  参考文献：
  名称：

  揭示大环 Gαq 蛋白抑制剂的结合机制和动力学

  摘要：

  G 蛋白代表细胞内开关，它转导从 G 蛋白偶联受体传递的信号。结构相关的大环缩肽 FR900359 (FR) 和 YM-254890 (YM) 是 Gα q蛋白家族的有效选择性抑制剂。我们最近发现放射性标记的 FR 和 YM 显示出强烈不同的停留时间，这意味着 FR 的抗哮喘作用明显更长。本研究旨在调查这种观察到的差异的分子基础。基于对接研究，我们突变了预测与 FR 或 YM 相互作用的 Gα q蛋白的氨基酸残基，并在含有天然 Gα q的细胞中重组表达了突变的 Gα q蛋白。蛋白质已被 CRISPR-Cas9 敲除。两种放射性配体显示出相似的结合动力学，并且它们的结合遵循构象选择机制，通过分子动力学模拟研究使其合理化。FR 的“亲脂性锚”的假定结合位点附近的氨基酸残基的几个突变，特别是那些预测与 FR 中存在的异丙基相互作用但 YM 中不存在的氨基酸残基，导致解离动力学显着加速。我们的数据表明，FR

  DOI：

  10.1016/j.phrs.2021.105880
• 作为产物：
  描述：

  在 2,4,6-三甲基吡啶 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以2.8 mg的产率得到YM-254890
  参考文献：
  名称：

  一系列选择性G蛋白抑制剂的总合成与构效关系研究

  摘要：

  G蛋白是G蛋白偶联受体信号传导的关键介质，它促进了许多重要的生理过程。环状双缩肽YM-254890和FR900359是G蛋白Gq亚家族中唯一已知的特异性抑制剂。但是，以前没有关于这些复杂天然产物的合成路线的报道，并且不容易从天然来源中分离出来。在这里，我们报告了YM-254890和FR900359以及两个已知类似物YM-385780和YM-385781的第一个全合成。合成方法的多功能性也使十种类似物的设计和合成成为可能，从而为此类化合物提供了首个结构-活性关系研究。G q-，G处所有化合物的药理学表征我-和G小号介导的信号提供了关于抑制的结构要求简洁信息，并证实这两种YM-254890和FR900359为G的高度有效的抑制剂q信令，与FR900359是最有效的。这些天然产物及其类似物代表着探索性研究G蛋白抑制作用的独特工具。

  DOI：

  10.1038/nchem.2577

文献信息

• Promoter‐Driven Overexpression in <i>Chromobacterium vaccinii</i> Facilitates Access to FR900359 and Yields Novel Low Abundance Analogs
  作者：Dominik Pistorius、Kathrin Buntin、Eric Weber、Etienne Richard、Caroline Bouquet、Séverine Wollbrett、Hugo Regenass、Victor Peón、Marcel Böhm、Régis Kessler、Thomas Gempeler、Anne Haberkorn、Laurin Wimmer、Christian Lanshoeft、John Davis、Dominik Hainzl、Joseph Anthony D'Alessio、Eusebio Manchado、Frank Petersen

  DOI：10.1002/chem.202103888

  日期：2022.2.7

  The promoter-driven overexpression of the frs biosynthetic gene cluster, encoding the nonribosomal peptide assembly line for FR900359, in Chromobacterium vaccinii resulted in up to 8-fold increase in production compared to the wild type. Thereby, the challenging access to FR could be significantly enhanced and novel low abundance analogs of FR were made accessible for characterization of their structures

  与野生型相比，在牛痘色杆菌中编码 FR900359 的非核糖体肽装配线的frs生物合成基因簇的启动子驱动过表达导致产量增加了 8 倍。因此，可以显着增强对 FR 的挑战性访问，并且可以使用新的低丰度 FR 类似物来表征它们的结构以及它们对葡萄膜黑色素瘤细胞系的生长抑制。
• YM-254890 analogues, novel cyclic depsipeptides with Gαq/11 inhibitory activity from Chromobacterium sp. QS3666
  作者：Masatoshi Taniguchi、Ken-ichi Suzumura、Koji Nagai、Tomihisa Kawasaki、Jun Takasaki、Mitsuhiro Sekiguchi、Yumiko Moritani、Tetsu Saito、Kazumi Hayashi、Shigeo Fujita、Shin-ichi Tsukamoto、Ken-ichi Suzuki

  DOI：10.1016/j.bmc.2004.04.006

  日期：2004.6

  The structure elucidation and biological activity of novel YM-254890 (1) analogues and semi-synthetic derivatives are described. Three natural analogues, YM-254891 (2), YM-254892 (3), and YM-280193 (4), were isolated from the fermentation broth of Chromobacterium sp. QS3666, and two hydrogenated derivatives, YM-385780 (5) and YM-385781 (6), were synthesized from YM-254890. Their structures were determined by one- and two-dimensional NMR studies and mass spectrometry. Among these compounds, two natural analogues 2-3 which possessed acyl groups at beta-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Galpha(q/11) inhibitory activity to that of 1. This indicates that the acyl beta-HyLeu residue plays an important role in activity and also that the alpha,beta-unsaturated carbonyl group of the N-MeDha residue is not critical to activity. The other hydrogenated derivative 5 had significantly less activity, which could be attributed to conformational differences. (C) 2004 Elsevier Ltd. All rights reserved.
• Compositions and Methods for Promoting Epithelialization and Wound Closure
  申请人：Tomic-Canic Marjana

  公开号：US20120289463A1

  公开（公告）日：2012-11-15

  Compositions for antagonizing phosphorylation and subsequent degradation of glycogen synthase kinase 3 beta (GSK3β) in epidermal cells are disclosed. GSK3β phosphorylation antagonists include molecules that function to inhibit or reduce the binding activity or enzymatic activity of an upstream signaling molecule leading to GSK3β phosphorylation, or by downregulating the expression of one or more upstream signaling molecules involved in regulating GSK3β phosphorylation. Methods of using the GSK3β phosphorylation antagonists to inhibit or reduce the phosphorylation and degradation of GSK3β in epidermal cells are provided. The methods are useful to promote epithelialization and closure of wounds, such as chronic non-healing wounds.
• ANTIBODIES TO PMEL17 AND CONJUGATES THEREOF
  申请人：NOVARTIS AG

  公开号：US20200197528A1

  公开（公告）日：2020-06-25

  This application discloses anti-PMEL17 antibodies, antigen binding fragments thereof, and antibody drug conjugates of said antibodies or antigen binding fragments conjugated to a GNAQ/GNA11 inhibitor. The invention also relates to methods of treating or preventing cancer using the antibodies, antigen binding fragments, and antibody drug conjugates. Also disclosed herein are methods of making the antibodies, antigen binding fragments, and antibody drug conjugates, and methods of using the antibodies and antigen binding fragments as diagnostic reagents.
• TARGETED PHARMACOLOGICAL THERAPEUTICS IN UVEAL MELANOMA
  申请人：Washington University

  公开号：US20200282015A1

  公开（公告）日：2020-09-10

  The present disclosure relates generally to methods and compositions for inhibiting or protecting against diseases arising from constitutively active G protein. In particular, the disclosure provides administration of FR900359, YM-254890 or a derivative thereof to down-regulate constitutively active G signaling, and is therefore useful in treatment for uveal melanoma, growth hormone-secreting pituitary tumors, tumors derived from Nevus of Ota, certain forms of other cancers (e.g. colon, lung, adenocarcinoma, skin melanoma, thyroid adenomas), cholera, Sturge-Weber Syndrome and other disorders.