5-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6-dimethoxyphenoxy)pentanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6-dimethoxyphenoxy)pentanoic acid
• 英文别名: 5-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-2,6-dimethoxy-phenoxy]-pentanoic acid；5-[4-[(2,4-diaminopyrimidin-5-yl)methyl]-2,6-dimethoxyphenoxy]pentanoic acid
• 化学式: C₁₈H₂₄N₄O₅
• 分子量: 376.412
• InChiKey: RWXBLUCACALTEE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  143
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6-dimethoxyphenoxy)pentanoic acid 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.08h， 生成
  参考文献：
  名称：

  Synthetic Self-Localizing Ligands That Control the Spatial Location of Proteins in Living Cells

  摘要：

  Small-molecule ligands that control the spatial location of proteins in living cells would be valuable tools for regulating biological systems. However, the creation of such molecules remains almost unexplored because of the lack of a design methodology. Here we introduce a conceptually new type of synthetic ligands, self-localizing ligands (SLLs), which spontaneously localize to specific subcellular regions in mammalian cells. We show that SLLs bind their target proteins and relocate (tether) them rapidly from the cytoplasm to their targeting sites, thus serving as synthetic protein translocators. SLL-induced protein translocation enables us to manipulate diverse synthetic/endogenous signaling pathways. The method is also applicable to reversible protein translocation and allows control of multiple proteins at different times and locations in the same cell. These results demonstrate the usefulness of SLLs in the spatial (and temporal) control of intracellular protein distribution and biological processes, opening a new direction in the design of small-molecule tools or drugs for cell regulation.

  DOI：

  10.1021/ja4046907
• 作为产物：
  描述：

  乙基5-碘戊酸酯 在 caesium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 5-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6-dimethoxyphenoxy)pentanoic acid
  参考文献：
  名称：

  Modulation of BCR Signaling by the Induced Dimerization of Receptor-Associated SYK

  摘要：

  多价抗原对 B 细胞抗原受体（BCR）的集聚作用通过 SYK 酪氨酸激酶传递给多种细胞内通路，这些通路决定了受体参与的生理后果。为了探索调节交联 BCR 信号数量和质量的因素，我们开发了一种新型二聚化化学介质，以诱导与受体相关的 SYK 聚合。为了实现这一目标，我们将 SYK 与大肠杆菌二氢叶酸还原酶（eDHFR）融合，后者能以高亲和力和选择性结合小分子三甲氧苄啶（TMP），并合成了带有柔性连接体的 TMP 二聚体。TMP 二聚体能在活细胞中诱导与 eDHFR 链接的 SYK 聚合。与 BCR 结合的 SYK 被诱导的二聚化会对下游转录因子的活化产生不同的调节作用，促进活化 T 细胞核因子（NFAT）的活化，而不影响 NFκB 的活化。SYK 的二聚化通过增强其与质膜上交联的 BCR 的相互作用程度和持续时间，增强了钙动员的持续时间而非幅度。

  DOI：

  10.3390/antib6040023

文献信息

• [EN] COMPOUNDS USEFUL FOR PROMOTING PROTEIN DEGRADATION AND METHODS USING SAME<br/>[FR] COMPOSÉS UTILES POUR STIMULER LA DÉGRADATION DES PROTÉINES ET PROCÉDÉS UTILISANT CEUX-CI
  申请人：UNIV YALE

  公开号：WO2013170147A1

  公开（公告）日：2013-11-14

  The present invention includes compounds that act as degraders of a target protein, wherein degradation is independent of the class of the target protein or its localization. In one embodiment, the invention comprises a compound comprising a protein degradation moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. The target protein contemplated within the invention comprises a posttranslational modified protein or intracellular protein. Compounds of the present invention may be used to treat disease states wherein protein degradation is a viable therapeutic approach, such as cancer or any sort of oxidative stress disease state.

  本发明包括作为目标蛋白质降解剂的化合物，其中降解与目标蛋白质的类别或其定位无关。在一种实施方式中，该发明包括一种化合物，其中蛋白质降解基团与连接剂共价结合，该化合物的ClogP等于或高于1.5。本发明中考虑的目标蛋白质包括后转录修饰蛋白质或细胞内蛋白质。本发明的化合物可用于治疗蛋白质降解是一种可行的治疗方法的疾病状态，如癌症或任何一种氧化应激疾病状态。
• Compounds Useful for Promoting Protein Degradation and Methods Using Same
  申请人：Yale University

  公开号：US20160022642A1

  公开（公告）日：2016-01-28

  The present description includes compounds that act as degraders of a target protein, wherein degradation is independent of the class of the target protein or its localization. In certain embodiments, the description includes a compound comprising a protein degradation moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. The target protein contemplated within the description comprises an androgen receptor. Compounds of the present description may be used to treat disease states wherein protein degradation is a viable therapeutic approach, such as cancer or any sort of oxidative stress disease state.

  本描述包括作为目标蛋白质降解剂的化合物，其中降解与目标蛋白质的类别或其定位无关。在某些实施例中，描述包括一种化合物，其中蛋白质降解基团与连接剂共价结合，该化合物的ClogP等于或高于1.5。描述中考虑的目标蛋白质包括雄激素受体。本描述的化合物可用于治疗蛋白质降解是可行治疗方法的疾病状态，如癌症或任何一种氧化应激疾病状态。
• SMALL MOLECULES FOR DUAL FUNCTION POSITRON EMISSION TOMOGRAPHY (PET) AND CELL SUICIDE SWITCHES
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US20190070321A1

  公开（公告）日：2019-03-07

  The present invention includes an engineered cell comprising a chimeric antigen receptor (CAR) further comprising a nucleic acid molecule comprising a suicide gene comprising a ligand binding domain and a suicide domain wherein the ligand binding domain is capable of binding to radiolabeled tracer or a small molecule suicide switch. This invention also includes methods for inducing apoptosis of an engineered cell, methods for assessing the efficacy or toxicity of an adoptive cell therapy in a subject, methods for detecting the quantity of engineered T cells in a subject, methods for monitoring an immunotherapy treatment in a subject and methods of imaging engineered T cells in a subject. In some embodiments, the imaging is performed via Positron Emission Topography (PET). This invention further includes a chemical inducer of dimerization (CID), wherein the CID is a Bis-Trimethoprim (Bis-TMP).

  本发明包括一种工程细胞，其中包括一个嵌合抗原受体（CAR），进一步包括一个包含自杀基因的核酸分子，该自杀基因包括一个配体结合结构域和一个自杀结构域，其中配体结合结构域能够结合到放射标记示踪剂或小分子自杀开关。该发明还包括诱导工程细胞凋亡的方法，评估在受试者中采用免疫细胞治疗的疗效或毒性的方法，检测受试者中工程T细胞的数量的方法，监测受试者中的免疫治疗方法以及在受试者中成像工程T细胞的方法。在某些实施例中，成像是通过正电子发射断层扫描（PET）进行的。该发明还包括一种化学诱导二聚体化合物（CID），其中CID是双三甲氧苄啶（Bis-TMP）。
• Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells
  作者：Bo Cai、Dongwook Kim、Saeed Akhand、Yixing Sun、Robert J. Cassell、Aktan Alpsoy、Emily C. Dykhuizen、Richard M. Van Rijn、Michael K. Wendt、Casey J. Krusemark

  DOI：10.1021/jacs.9b08085

  日期：2019.10.30

  of DNA-encoded small molecule libraries against protein targets within the cytosol and on the surface of live cells. The approach relies on generation of a covalent linkage of the DNA to protein targets by affinity labeling. This crosslinking event enables subsequent co-purification by a tag on the recombinant protein. To access targets within cells, a cyclic cell-penetrating peptide is appended to

  我们报告了针对细胞质内和活细胞表面的蛋白质靶标的 DNA 编码小分子文库的选择。该方法依赖于通过亲和标记产生 DNA 与蛋白质靶标的共价连接。这种交联事件能够通过重组蛋白上的标签进行后续的共纯化。为了访问细胞内的目标，循环细胞穿透肽被附加到 DNA 编码的文库中，以便跨细胞膜传递。由于这种方法评估了 DEL 与活细胞中靶标的结合，因此它提供了一种针对无法表达和纯化为活性的挑战性靶标的 DEL 选择策略。
• Alternative Reagents for Methotrexate as Immobilizing Anchor Moieties in the Optimization of MASPIT: Synthesis and Biological Evaluation
  作者：Dries J. H. De Clercq、Martijn D. P. Risseeuw、Izet Karalic、Anne-Sophie De Smet、Dieter Defever、Jan Tavernier、Sam Lievens、Serge Van Calenbergh

  DOI：10.1002/cbic.201402702

  日期：2015.3.23

  Cast the anchor: Two chemical dimerizer approaches, TMP‐ and SNAP‐tag, were evaluated so as to increase the sensitivity of a system that enables small‐molecule target protein profiling in intact human cells. Fusion compounds of tamoxifen tethered to a prokaryote‐specific DHFR ligand produced dose–response curves shifted towards significantly lower EC50 values than those of the original MTX congeners

  抛锚：对两种化学二聚体方法（TMP和SNAP标签）进行了评估，以提高系统的灵敏度，该系统可在完整的人类细胞中进行小分子靶蛋白分析。他莫昔芬的融合化合物与原核生物特异的DHFR配体束缚在一起，产生的剂量反应曲线向EC 50值明显降低，比原始MTX同系物的EC 50值低。