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| 5mg |
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| Targets |
The compound targets cereblon (CRBN), a component of the CUL4-RBX1-DDB1-CRBN E3 ubiquitin ligase complex. The thalidomide-derived moiety binds to CRBN, recruiting the E3 ligase machinery. When this CRBN ligand is conjugated to a target protein ligand via the C9 linker, the resulting PROTAC molecule brings the target protein into proximity with the E3 ligase, leading to target ubiquitination and subsequent proteasomal degradation. The C9 alkyl linker is fully hydrophobic, providing a different property profile compared to PEG-based linkers, which may be optimal for targets requiring specific spatial configurations.
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| ln Vitro |
In vitro activity of this compound is realized through its use as a PROTAC building block. When conjugated to a target protein-binding ligand, the resulting PROTAC induces target protein ubiquitination and proteasome-dependent degradation. The ligand-linker conjugate alone exhibits minimal intrinsic biological activity. In cell-based assays, PROTACs constructed with C9 alkyl linkers have been shown to effectively degrade various target proteins. Typical validation involves treating cells with the PROTAC at concentrations ranging from 0.001-10 uM for 4-24 hours, followed by Western blot analysis to quantify target protein levels. Dose-response curves yield DC50 values that depend on the specific target protein and the geometry of the ternary complex formed between CRBN, the PROTAC, and the target.
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| ln Vivo |
In vivo efficacy studies with PROTACs incorporating the C9 linker are typically conducted in murine xenograft models. Complete PROTAC molecules are administered to tumor-bearing immunodeficient mice via intraperitoneal (IP) or intravenous (IV) routes at doses ranging from 1-30 mg/kg. Dosing frequency is typically daily or every other day for 2-4 weeks. The hydrophobic C9 alkyl linker may reduce aqueous solubility compared to PEG-based linkers, often requiring formulation with co-solvents such as DMSO, PEG300, or cyclodextrins for adequate solubility. Efficacy is assessed by tumor volume measurements, Western blot analysis of target protein degradation in harvested tumor tissues, and evaluation of pharmacodynamic markers.
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| Enzyme Assay |
CRBN-binding affinity of the thalidomide-5-O component can be measured using surface plasmon resonance (SPR) or fluorescence polarization (FP) competitive binding assays. For SPR, purified CRBN-DDB1 complex is immobilized on a sensor chip, and varying concentrations of the compound are tested to determine binding kinetics and affinity. For FP, a fluorescently labeled thalidomide probe is used in competition with the test compound. Typical assay buffer: 50 mM HEPES (pH 7.4), 150 mM NaCl, 1 mM DTT, 0.01% Tween-20, 0.1 mg/mL BSA. The C9 linker attached at the 5-O position does not interfere with the CRBN binding interface, as this position is a known attachment site in PROTAC design. Thalidomide-based ligands typically exhibit KD values in the low micromolar range.
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| Cell Assay |
To construct a PROTAC, the terminal primary amine of this compound is conjugated to a target protein ligand containing a carboxylic acid group via standard amide coupling chemistry. Typical procedure: The target ligand carboxylic acid (1.0 equiv) is dissolved in anhydrous DMF or DMSO with HATU or EDCI/HOBt (1.2 equiv) and DIPEA (2-3 equiv) and activated for 10-30 minutes. The amine linker (1.0-1.2 equiv) is added, and the reaction is stirred at room temperature for 2-12 hours. The resulting PROTAC is purified by preparative HPLC and characterized by LC-MS and NMR. For cellular activity assays, cells are treated with the PROTAC (0.001-10 uM, 4-24 h) followed by Western blotting to assess target degradation.
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| Animal Protocol |
In vivo animal studies with PROTACs containing this C9 linker follow standard xenograft protocols. Immunodeficient mice (6-8 weeks old, n=5-10 per group) bearing subcutaneous human tumor xenografts are randomized into treatment groups when tumors reach approximately 100-200 mm3. PROTACs are formulated in a vehicle appropriate for hydrophobic compounds (e.g., 10% DMSO, 40% PEG300, 5% Tween 80, 45% saline; or 10% DMSO, 90% corn oil) and administered IP or IV at 1-30 mg/kg. Dosing frequency ranges from once daily to three times weekly. Tumor volumes (measured by calipers) and body weights are recorded every 2-3 days. At study termination, tumors are harvested for Western blot or IHC analysis of target protein degradation. Plasma samples are collected for PK analysis by LC-MS/MS.
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| ADME/Pharmacokinetics |
For the standalone ligand-linker conjugate, the C9 alkyl linker (9 carbons) is hydrophobic, contributing to increased lipophilicity (higher logP) compared to PEG-based linkers. When incorporated into PROTACs, the hydrophobic C9 linker may affect pharmacokinetic properties including reduced aqueous solubility, increased plasma protein binding, potentially longer half-life due to reduced clearance, but also increased risk of non-specific binding and off-target effects. The hydrochloride salt form improves water solubility and stability for handling and storage. PROTACs containing alkyl linkers often require formulation with organic solvents or surfactants for in vivo administration. No dedicated PK studies are available for the ligand-linker conjugate alone as it is a synthetic intermediate.
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| Toxicity/Toxicokinetics |
Toxicology data specific to Thalidomide-5-O-C9-NH2 hydrochloride is not publicly available. As a thalidomide-derived CRBN ligand, the compound shares the core structure responsible for teratogenic effects. The hydrophobic C9 alkyl linker does not alter this risk. Researchers should handle thalidomide-derived compounds with extreme caution, particularly regarding potential developmental toxicity. Pregnant or potentially pregnant individuals should avoid direct handling. Standard chemical safety practices must be followed: work in a chemical fume hood, wear appropriate PPE (nitrile gloves, lab coat, safety glasses), avoid inhalation or ingestion, wash hands thoroughly after handling. This product is for research use only, not for human or therapeutic use.
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| Additional Infomation |
Thalidomide-5-O-C9-NH2 hydrochloride is part of a series of thalidomide-based CRBN ligands with alkyl linkers of varying lengths (C7, C8, C9, C10, C11, C12, C13, C14) for PROTAC optimization studies. The C9 length provides a moderate spacer that may be optimal for target proteins requiring an intermediate distance between CRBN and the target binding site. The mechanism of action involves recruitment of cereblon and facilitation of target protein ubiquitination and degradation via the proteasome. This compound is strictly a research chemical tool, not an approved drug, and has not been evaluated in clinical trials. It is intended for laboratory research applications including targeted protein degradation, cancer biology, and chemical biology. Storage: powder at -20degC, protected from light and moisture, under inert atmosphere.
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| Molecular Formula |
C22H30CLN3O5
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| Molecular Weight |
451.94
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| Appearance |
White to off-white solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2127 mL | 11.0634 mL | 22.1268 mL | |
| 5 mM | 0.4425 mL | 2.2127 mL | 4.4254 mL | |
| 10 mM | 0.2213 mL | 1.1063 mL | 2.2127 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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