| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
CDK4 (Cyclin-dependent kinase 4), CDK6 (Cyclin-dependent kinase 6)
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|---|---|
| ln Vitro |
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as tracers for quantification throughout the drug development process. Due to its potential to alter the pharmacokinetic and metabolic characteristics of medications, deuteration has drawn attention[1].
This deuterated compound is a CDK inhibitor with anti-tumor activity. It is less potent than the parent abemaciclib and the M2 metabolite. It can be used in combination with a CRBN ligand to design PROTAC (proteolysis-targeting chimera) molecules for the targeted degradation of CDK4/6 proteins. |
| ln Vivo |
As a circulating metabolite of abemaciclib, it contributes to the overall in vivo efficacy of the parent drug. Its plasma concentrations reach steady state after multiple doses. It has a longer half-life compared to the parent drug, contributing to sustained target inhibition and prolonged anti-tumor activity.
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| Enzyme Assay |
In a standard enzymatic assay, recombinant CDK4/Cyclin D1 or CDK6/Cyclin D3 is incubated with a peptide substrate and ATP in a reaction buffer. The internal standard, M18-d8, is added to samples for normalization. The reaction is terminated, and the incorporation of phosphate into the substrate is measured using a luminescent ADP detection kit or a radiometric assay. IC50 values are calculated.
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| Cell Assay |
For PROTAC studies, a specific cell line (e.g., MCF-7 or T-47D) is treated with a PROTAC molecule that incorporates the M18 warhead. After treatment for 6-24 hours, cells are lysed. The protein concentrations are determined. The lysates are then subjected to Western blot analysis using antibodies against CDK4, CDK6, and a loading control (e.g., GAPDH or beta-actin). The degradation efficiency is quantified by densitometry.
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| Animal Protocol |
In a mouse xenograft model, immunodeficient mice are implanted with human cancer cells. Once tumors are established, the animals are orally administered a PROTAC CDK4/6 degrader that uses the M18 ligand. At the end of the study, blood and tumor tissue are collected. The concentration of the degrader in the samples is measured by LC-MS using M18-d8 as an internal standard. Tumor growth is measured to evaluate efficacy.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in humans have shown that M18 is a major circulating metabolite of abemaciclib. It has a long terminal half-life, which is longer than the parent drug. The exposure (AUC) of M18 is comparable to that of the parent drug, making it a significant contributor to the drug's pharmacological effect. Deuteration can alter these PK parameters.
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| Toxicity/Toxicokinetics |
Abemaciclib is an approved drug (Verzenio®) for breast cancer. Its known toxicities include diarrhea, neutropenia, fatigue, and nausea. The M18 metabolite is expected to contribute to these adverse effects, particularly neutropenia. The deuterated form is not intended for human use and shares the same toxicity profile if used at pharmacological doses.
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| References |
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| Additional Infomation |
PROTACs are an emerging therapeutic modality that uses the body's natural protein degradation machinery to remove disease-causing proteins. The M18 metabolite is a key pharmacophore in the development of CDK4/6 degraders. This isotope-labeled product is an essential research tool for quantifying these novel degraders in biological samples.
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| Molecular Formula |
C25H20D8F2N8O
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|---|---|
| Molecular Weight |
502.59
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| Related CAS # |
Abemaciclib metabolite M18 hydrochloride;2704316-82-3;Abemaciclib metabolite M18;2704316-81-2
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| Appearance |
Off-white to light 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) |
DMSO :~32 mg/mL (~63.67 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.78 mg/mL (3.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 17.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1.78 mg/mL (3.54 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 17.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9897 mL | 9.9485 mL | 19.8969 mL | |
| 5 mM | 0.3979 mL | 1.9897 mL | 3.9794 mL | |
| 10 mM | 0.1990 mL | 0.9948 mL | 1.9897 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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