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| Targets |
The compound targets cereblon (CRBN), an E3 ubiquitin ligase substrate receptor within the CUL4-RBX1-DDB1-CRBN complex. The thalidomide-derived ligand binds to CRBN, recruiting the E3 ubiquitin ligase machinery. When conjugated to a target protein ligand via the long C14 linker, the resulting PROTAC molecule brings the target protein into proximity with the E3 ligase, facilitating target ubiquitination and subsequent proteasomal degradation. The extended C14 alkyl linker provides maximal distance between the CRBN ligand and the conjugated target ligand, which may be essential for target proteins where the CRBN binding site and the target binding epitope are far apart.
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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 C14 alkyl linkers have been evaluated for degradation of various target proteins requiring long reach. Standard 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. The long C14 linker may be essential for optimal ternary complex formation with certain target proteins.
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| ln Vivo |
In vivo efficacy studies with PROTACs incorporating the C14 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 highly hydrophobic C14 alkyl linker (14 carbons) significantly reduces aqueous solubility, requiring specialized formulation with co-solvents such as DMSO, PEG300, Tween 80, cyclodextrins, or lipid-based formulations 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 biomarkers.
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| Enzyme Assay |
CRBN-binding affinity of the thalidomide-5-O component can be measured using fluorescence polarization (FP) or surface plasmon resonance (SPR). For FP competitive binding assays, purified CRBN-DDB1 complex is incubated with a fluorescently labeled thalidomide probe and varying concentrations of the test compound. IC50 values are determined by measuring probe displacement. Typical assay conditions: 50 mM HEPES (pH 7.4), 150 mM NaCl, 1 mM DTT, 0.01% Tween-20, 0.1 mg/mL BSA. The long C14 linker attached at the 5-O position does not interfere with the CRBN binding interface, as this position is a standard attachment point in PROTAC design. Thalidomide-based CRBN ligands typically exhibit KD values in the low micromolar range (approximately 1-10 uM).
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| Cell Assay |
To construct a PROTAC molecule, the terminal primary amine of this compound is conjugated to a target protein ligand containing a carboxylic acid via standard amide coupling chemistry. General protocol: The target ligand carboxylic acid (1.0 equiv) is dissolved in anhydrous DMF or DMSO, then HATU or EDCI/HOBt (1.2 equiv) and DIPEA (2-3 equiv) are added and the mixture is stirred for 10-30 minutes at room temperature. The amine linker (1.0-1.2 equiv) is then added, and the reaction is stirred for 2-12 hours. The resulting PROTAC is purified by preparative HPLC and characterized by LC-MS. For cellular activity validation, cells are treated with the PROTAC (0.001-10 uM, 4-24 h), then lysed and analyzed by Western blotting to assess target protein degradation.
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| Animal Protocol |
In vivo animal studies with PROTACs containing the C14 linker follow standard xenograft protocols with special attention to formulation. Immunodeficient mice (nude or NSG, 6-8 weeks old, n=5-10 per group) bearing subcutaneous human tumor xenografts (approximately 100-200 mm3) are randomized into treatment groups. PROTACs are formulated in a vehicle suitable for highly hydrophobic compounds (e.g., 10% DMSO, 40% PEG300, 5% Tween 80, 45% saline; or 10% DMSO, 90% corn oil; or cyclodextrin-based formulations) and administered IP or IV at 1-30 mg/kg. Dosing frequency ranges from once daily to three times weekly. Tumor volumes and body weights are recorded every 2-3 days. At study termination (2-4 weeks), tumors are harvested for Western blot or IHC analysis of target protein degradation, and plasma is collected for PK analysis.
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| ADME/Pharmacokinetics |
For the standalone ligand-linker conjugate, the C14 alkyl linker is highly hydrophobic, contributing to very low aqueous solubility (<0.1 mg/mL in simple buffers) and high lipophilicity (high logP). When incorporated into PROTACs, the C14 linker significantly increases overall lipophilicity, which may affect pharmacokinetic properties including very limited aqueous solubility (requiring specialized formulations), high plasma protein binding (>99% typical), potentially prolonged half-life due to slow clearance, but also increased risk of non-specific tissue binding and off-target toxicity. The hydrochloride salt form improves handling solubility to some extent, but substantial formulation is required for in vivo administration. No dedicated PK studies are available for the ligand-linker conjugate alone. PROTACs containing long alkyl linkers typically require parenteral administration and may show altered distribution profiles.
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| Toxicity/Toxicokinetics |
Toxicology data specific to Thalidomide-5-O-C14-NH2 hydrochloride is not publicly available. Thalidomide and its derivatives are known teratogens causing severe birth defects via CRBN binding. The long hydrophobic C14 linker does not eliminate this risk. Additionally, highly lipophilic compounds may have increased potential for tissue accumulation and off-target toxicity. Researchers must handle this compound with extreme caution: work in a chemical fume hood, wear appropriate PPE (gloves, lab coat, safety glasses, face shield), avoid skin contact, inhalation, and ingestion. Pregnant or potentially pregnant individuals should avoid handling. This product is for research use only; not for human use, therapeutic applications, or diagnostic purposes.
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| Additional Infomation |
Thalidomide-5-O-C14-NH2 hydrochloride is a research tool for PROTAC-based targeted protein degradation. The C14 linker is the longest in the C7-C14 alkyl linker series, providing maximal spatial separation between the CRBN ligand and the conjugated target ligand. This extended reach may be essential for degrading target proteins where the CRBN binding site and the target binding epitope are far apart in the ternary complex. The compound is strictly for laboratory research applications including chemical biology, targeted protein degradation optimization, cancer research, and drug discovery. It has not been evaluated in clinical trials and is not an approved drug. Storage: powder at -20degC, protected from light and moisture, under inert atmosphere.
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| Molecular Formula |
C27H40CLN3O5
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| Molecular Weight |
522.08
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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 | 1.9154 mL | 9.5771 mL | 19.1542 mL | |
| 5 mM | 0.3831 mL | 1.9154 mL | 3.8308 mL | |
| 10 mM | 0.1915 mL | 0.9577 mL | 1.9154 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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