E3 ligase Ligand 3
(Synonyms: Cereblon ligand 3; E3 ligase Ligand 3) 目录号 : GC30029
A PROTAC building block
Cas No.:1061605-21-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Cereblon ligand 1 is a building block in the synthesis of proteolysis-targeting chimera technologies (PROTACs).1
1.Lohbeck, J., and Miller, A.K.Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC developmentBioorg. Med. Chem. Lett.26(21)5260-5262(2016)
| Cas No. | 1061605-21-7 | SDF | |
| 别名 | Cereblon ligand 3; E3 ligase Ligand 3 | ||
| Canonical SMILES | O=C(N(C(CCC1=O)C(N1)=O)C2=O)C(C2=CC=C3)=C3OCC(O)=O | ||
| 分子式 | C15H12N2O7 | 分子量 | 332.26 |
| 溶解度 | DMSO : ≥ 42 mg/mL (126.41 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0097 mL | 15.0485 mL | 30.0969 mL |
| 5 mM | 0.6019 mL | 3.0097 mL | 6.0194 mL |
| 10 mM | 0.301 mL | 1.5048 mL | 3.0097 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
E3 ligase ligand chemistries: from building blocks to protein degraders
Chem Soc Rev.2022 May 10;51(9):3487-3534.PMID:35393989DOI: 10.1039/d2cs00148a.
In recent years, proteolysis-targeting chimeras (PROTACs), capable of achieving targeted protein degradation, have proven their great therapeutic potential and usefulness as molecular biology tools. These heterobifunctional compounds are comprised of a protein-targeting ligand, an appropriate linker, and a ligand binding to the E3 ligase of choice. A successful PROTAC induces the formation of a ternary complex, leading to the E3 ligase-mediated ubiquitination of the targeted protein and its proteasomal degradation. In over 20 years since the concept was first demonstrated, the field has grown substantially, mainly due to the advancements in the discovery of non-peptidic E3 ligase ligands. Development of small-molecule E3 binders with favourable physicochemical profiles aided the design of PROTACs, which are known for breaking the rules of established guidelines for discovering small molecules. Synthetic accessibility of the ligands and numerous successful applications led to the prevalent use of cereblon and von Hippel-Lindau as the hijacked E3 ligase. However, the pool of over 600 human E3 ligases is full of untapped potential, which is why expanding the artillery of E3 ligands could contribute to broadening the scope of targeted protein degradation. In this comprehensive review, we focus on the chemistry aspect of the PROTAC design process by providing an overview of liganded E3 ligases, their chemistries, appropriate derivatisation, and synthetic approaches towards their incorporation into heterobifunctional degraders. By covering syntheses of both established and underexploited E3 ligases, this review can serve as a chemistry blueprint for PROTAC researchers during their future ventures into the complex field of targeted protein degradation.
Sweet and Blind Spots in E3 Ligase Ligand Space Revealed by a Thermophoresis-Based Assay
ACS Med Chem Lett.2020 Dec 4;12(1):74-81.PMID:33488967DOI: 10.1021/acsmedchemlett.0c00440.
Repurposing E3 ubiquitin ligases for targeted protein degradation via customized molecular glues or proteolysis-targeting chimeras (PROTACs) is an increasingly important therapeutic modality. Currently, a major limitation in the design of suitable molecular glues and PROTACs is our fragmentary understanding of E3 ligases and their ligand space. We here describe a quantitative assay for the discovery and characterization of E3 ligase ligands that is based on the thermophoretic behavior of a custom reporter ligand. Thereby, it is orthogonal to commonly employed fluorescence-based assays and less affected by the optical properties of test compounds. It can be employed for the high-throughput screening of compound libraries for a given ligase but also for hit validation, which we demonstrate with the identification of unexpected well-binders and non-binders, yielding new insights into the ligand space of cereblon (CRBN).
Discovery of E3 Ligase Ligands for Target Protein Degradation
Molecules.2022 Oct 2;27(19):6515.PMID:36235052DOI: 10.3390/molecules27196515.
Target protein degradation has emerged as a promising strategy for the discovery of novel therapeutics during the last decade. Proteolysis-targeting chimera (PROTAC) harnesses a cellular ubiquitin-dependent proteolysis system for the efficient degradation of a protein of interest. PROTAC consists of a target protein ligand and an E3 ligase ligand so that it enables the target protein degradation owing to the induced proximity with ubiquitin ligases. Although a great number of PROTACs has been developed so far using previously reported ligands of proteins for their degradation, E3 ligase ligands have been mostly limited to either CRBN or VHL ligands. Those PROTACs showed their limitation due to the cell type specific expression of E3 ligases and recently reported resistance toward PROTACs with CRBN ligands or VHL ligands. To overcome these hurdles, the discovery of various E3 ligase ligands has been spotlighted to improve the current PROTAC technology. This review focuses on currently reported E3 ligase ligands and their application in the development of PROTACs.
Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery
Bioorg Chem.2022 Aug;125:105848.PMID:35533582DOI: 10.1016/j.bioorg.2022.105848.
Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.
PROTACs in gastrointestinal cancers
Mol Ther Oncolytics.2022 Nov 3;27:204-223.PMID:36420306DOI: 10.1016/j.omto.2022.10.012.
Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.