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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, inducing a conformational change that promotes the recruitment and ubiquitination of neo-substrates. This binding mechanism is the foundation for PROTAC technology. The long C14 alkyl linker provides substantial distance between the CRBN ligand and the conjugated target ligand, which can be advantageous when target proteins require a large spatial separation from the E3 ligase for optimal ternary complex formation and degradation efficiency.
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| ln Vitro |
In vitro activity of this compound is demonstrated as a PROTAC building block. When conjugated to a target protein-binding ligand via amide coupling using the terminal amine, the resulting PROTAC molecule recruits CRBN to the target protein, leading to target ubiquitination and proteasomal degradation. The ligand-linker conjugate itself shows minimal standalone biological activity. In cell-based assays, PROTACs constructed with this linker have been shown to effectively reduce target protein levels (e.g., Myc, BRD4, BTK) in cancer cell lines at nanomolar concentrations, leading to decreased cell proliferation and increased apoptosis rates as demonstrated in proof-of-concept studies.
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| ln Vivo |
In vivo studies with PROTACs incorporating the C14 linker are typically conducted in murine xenograft models of cancer. Complete PROTAC molecules are administered via intraperitoneal or intravenous routes at doses typically ranging from 5-30 mg/kg, often on a daily or every-other-day schedule for 2-4 weeks. The long C14 alkyl linker provides extended reach, which may be essential for engaging certain target proteins that are positioned far from the CRBN binding site in the ternary complex. Efficacy endpoints include tumor growth inhibition, target protein degradation assessed by Western blotting of tumor tissue, and evaluation of downstream pharmacodynamic markers.
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| Enzyme Assay |
For in vitro binding assays, CRBN-binding affinity can be measured using fluorescence polarization (FP) or surface plasmon resonance (SPR). Purified CRBN-DDB1 complex is immobilized, and varying concentrations of the compound are tested to determine KD values. Competitive binding assays using a fluorescently labeled thalidomide probe can determine IC50 values. 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 does not significantly affect CRBN binding affinity as the linker is attached at a position that does not interfere with the CRBN-binding interface.
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| Cell Assay |
To construct a PROTAC molecule using this building block, the primary amine group is conjugated to a target protein ligand containing a carboxylic acid via standard amide coupling chemistry using HATU or EDCI/HOBt with a base (DIPEA) in DMF or DMSO. The resulting PROTAC is purified by preparative HPLC. For cellular activity validation, target cells are treated with the PROTAC (0.001-10 uM, 4-24 h), followed by Western blot to assess target protein degradation. Concentration-dependent degradation (DC50) and maximal degradation (Dmax) are determined. Control treatments include the unconjugated target ligand, the unconjugated CRBN ligand, and a PROTAC with an inactive linker to confirm degradation is dependent on both binding functionalities.
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| Animal Protocol |
In vivo animal studies with PROTACs containing this C14 linker follow standard xenograft protocols. Immunodeficient mice (nude or NSG, 6-8 weeks old, n=5-10 per group) bearing subcutaneous tumors are dosed with PROTACs via IP or IV injection (1-30 mg/kg, daily or QOD). Tumor volumes measured by calipers and body weights are recorded every 2-3 days. Plasma and tumor samples are collected at various time points for PK/PD analysis. Target protein knockdown in tumors is confirmed by Western blot or IHC. The long alkyl linker (C14) is highly hydrophobic, which may reduce aqueous solubility and affect in vivo pharmacokinetics, often requiring formulation with co-solvents such as PEG300 or cyclodextrins for adequate solubility.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of PROTACs incorporating this linker depend on the overall molecular properties, but the long hydrophobic C14 alkyl chain (14 carbons) contributes to increased lipophilicity (higher logP) compared to PEG-based linkers, which may affect absorption, distribution, and clearance. High lipophilicity can increase plasma protein binding, reduce aqueous solubility, and potentially prolong half-life. However, increased lipophilicity may also lead to off-target accumulation and toxicity concerns. The hydrochloride salt form improves water solubility and stability during storage and handling. For the ligand-linker conjugate alone (molecular weight approximately 521 g/mol), no dedicated PK studies are available as it is a synthetic intermediate rather than a directly dosed entity.
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| Toxicity/Toxicokinetics |
Toxicology data specific to Thalidomide-NH-C14-NH2 hydrochloride is not publicly available. As a thalidomide derivative, the compound shares structural features with thalidomide, which has well-established teratogenic effects causing severe birth defects. The cereblon-binding activity responsible for therapeutic immunomodulatory effects is also responsible for teratogenicity. Therefore, any thalidomide-derived compound should be handled with extreme caution regarding potential developmental toxicity. Researchers, particularly women of childbearing potential, should avoid direct contact, inhalation, or ingestion. Standard chemical safety practices (gloves, lab coat, eye protection, fume hood) must be followed. For research use only; not for human or therapeutic use.
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| Additional Infomation |
Thalidomide-NH-C14-NH2 hydrochloride is a specialized chemical tool for targeted protein degradation research via PROTAC technology. The long C14 alkyl diamino linker provides extended reach, enabling degradation of target proteins that are inaccessible with shorter linkers. This compound falls under the classification of cytokine inhibitory drugs designed to modulate inflammatory processes. The mechanism of action involves inhibition of tumor necrosis factor-alpha (TNF-alpha) and modulation of immune responses. In cancer research, such PROTACs are investigated as part of combination therapies for multiple myeloma and other malignancies. The compound has not been evaluated in clinical trials and is not an approved drug. It is intended exclusively for laboratory research applications in chemical biology, cancer biology, and drug discovery.
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| Molecular Formula |
C27H41CLN4O4
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| Molecular Weight |
521.09
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| Appearance |
Light yellow to green yellow 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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 | 1.9191 mL | 9.5953 mL | 19.1905 mL | |
| 5 mM | 0.3838 mL | 1.9191 mL | 3.8381 mL | |
| 10 mM | 0.1919 mL | 0.9595 mL | 1.9191 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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