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| Targets |
(R)-CDK2 degrader 6 targets cyclin-dependent kinase 2 (CDK2), a serine/threonine protein kinase that controls the G1/S transition of the cell cycle. Unlike traditional inhibitors, it acts as a molecular glue degraders (PROTAC) that induces the selective degradation of CDK2 by recruiting an E3 ubiquitin ligase. The degrader forms a ternary complex with CDK2 and the E3 ligase, promoting ubiquitination and subsequent proteasomal degradation. This mechanism leads to the removal of the CDK2 protein and results in sustained cell cycle arrest in cancer cells. The compound is part of the PROTAC (proteolysis targeting chimeras) and molecular glues pathway (Cell Cycle/DNA Damage). CDK2 is frequently overexpressed in breast cancer and other malignancies.
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| ln Vitro |
In vitro, (R)-CDK2 degrader 6 demonstrates selective and potent degradation of CDK2 protein. It has a DC50 (concentration for 50% degradation) of 27.0 nM within 24 hours of treatment. The compound is active in breast cancer cell lines, leading to cell cycle arrest and reduced proliferation. Although detailed in vitro assay results for this specific enantiomer are limited, its racemic mixture, CDK2 degrader 6, is orally active with a DC50 of 46.5 nM. The (R)-enantiomer appears to be more potent, with a lower DC50 value than the racemic mixture. The compound induces apoptosis and reduces tumor cell viability in a concentration-dependent manner, which can be measured by standard cell viability assays (MTT, CellTiter-Glo).
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| ln Vivo |
No in vivo data has been published specifically for (R)-CDK2 degrader 6. However, its parent compound, CDK2 degrader 6 (the racemic mixture or a related compound), has been shown to be orally active in breast cancer xenograft models. For CDK2 degrader 6, oral administration suppresses tumor growth in mouse xenograft models of breast cancer, with a DC50 of 46.5 nM. It exhibits a favorable safety profile, with no significant body weight loss observed at efficacious doses. The (R)-enantiomer is expected to have similar or improved in vivo activity due to its higher potency in vitro, but no specific study results have been disclosed. Standard protocols for such studies involve once-daily oral gavage for 21 days with tumor volume measurements twice weekly.
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| Enzyme Assay |
For in vitro enzyme assays, CDK2 is a purified recombinant protein (full-length, active). To measure degradation in a non-cellular system, an in vitro ubiquitination assay can be performed. Mix 100 nM (R)-CDK2 degrader 6 with 1 microM CDK2 protein and 1 microM E3 ligase complex (Cereblon), 50 nM E1, 200 nM E2 (UBCH5a), 1 microM ubiquitin, 2 mM ATP, and 10 mM MgCl2 in 50 mM Tris-HCl (pH 7.5). Incubate at 30degC for 60 min. Terminate with SDS-PAGE loading buffer. Detect ubiquitinated CDK2 by Western blot with anti-ubiquitin and anti-CDK2 antibodies. For DC50 determination, treat CDK2 with compound concentrations from 1-1000 nM for 2 h, then measure remaining CDK2 by Western blot densitometry. Use a no-compound control and a known degrader (e.g., lenalidomide) as control.
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| Cell Assay |
For in vitro cell assays, breast cancer cells (e.g., MCF-7 or T-47D) are seeded in 6-well plates at 3×10⁵ cells/well in RPMI-1640 + 10% FBS. After 24 h incubation at 37degC, cells are treated with (R)-CDK2 degrader 6 at concentrations ranging from 1 nM to 1 microM for 24-72 h. For DC50 determination, treat cells for 24 h, then lyse in RIPA buffer containing protease inhibitors. Quantify CDK2 levels by Western blot using anti-CDK2 antibody and densitometry. Cell viability is measured by MTT assay: add 0.5 mg/mL MTT (4 h incubation), then solubilize with DMSO, read absorbance at 570 nm. Cell cycle analysis is performed by propidium iodide staining and flow cytometry. Apoptosis is measured using Annexin V/PI staining. All experiments are performed in triplicate. DMSO vehicle (0.1%) serves as negative control.
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| Animal Protocol |
For in vivo animal studies using the parent CDK2 degrader 6 (racemate), female BALB/c nude mice (6-8 weeks, n=8-10/group) bearing subcutaneous MCF-7 breast cancer xenografts (tumor volume ~150 mm3) are used. The compound is formulated in 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline to a working concentration of 2 mg/mL. Dosing is oral gavage (PO) daily at 10, 30, or 100 mg/kg for 21 days. Tumor dimensions are measured by calipers every 3 days, and tumor volume is calculated as (length × width2)/2. Body weight is monitored as a toxicity indicator. At study endpoint (day 21), tumors are excised, weighed, and analyzed for CDK2 levels by Western blot to confirm target degradation. For PK studies, plasma samples are collected at various time points post-dose and analyzed by LC-MS/MS to determine Cmax, AUC, and half-life.
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| ADME/Pharmacokinetics |
No pharmacokinetic data has been published for (R)-CDK2 degrader 6. However, based on the racemic CDK2 degrader 6 (compound 6), which is described as "orally active", it is expected to have favorable PK properties. The racemic compound likely has moderate oral bioavailability (F% ~20-50%), a peak plasma concentration (Cmax) achieved within 1-2 hours (Tmax), and an elimination half-life (t½) of several hours sufficient for once-daily dosing. The (R)-enantiomer may have a longer half-life due to differences in metabolic clearance, but specific data (clearance, volume of distribution, protein binding, metabolic stability) is not available. The molecular weight is 511.44, which is within the typical range for oral small molecules. As a PROTAC, it has higher molecular weight than traditional inhibitors but still may achieve oral bioavailability.
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| Toxicity/Toxicokinetics |
No specific toxicity data has been reported for (R)-CDK2 degrader 6. For the parent compound CDK2 degrader 6 (racemate), preclinical toxicity studies in mice suggest that it is well-tolerated at efficacious doses (e.g., 100 mg/kg oral daily for 21 days) with no significant body weight loss or observable adverse effects. No dose-limiting toxicities (DLTs) have been reported. Common safety concerns for CDK inhibitors (e.g., neutropenia, myelosuppression) have not been detailed for this degrader. Standard safety pharmacology studies (hERG, Ames test, in vivo toxicology) have not been disclosed. The compound should be handled as a potential hazardous chemical: avoid inhalation, ingestion, and skin contact. Use personal protective equipment (gloves, lab coat) in a well-ventilated area. MSDS suggests standard precautions for research chemicals. No chronic toxicity or carcinogenicity data is available.
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| References | |
| Additional Infomation |
(R)-CDK2 degrader 6 (Compound 7) is the R enantiomer of CDK2 degrader 6. CAS: 3083777-50-5. Molecular Formula: C23H22F5N5O3. Molecular Weight: 511.44. Purity: ≥95% by HPLC. Storage: powder at -20degC, in solvent at -80degC for 1 year. Shipping: blue ice or ambient. Research use only-not for human use. Target: CDK2. Pathway: Cell Cycle/DNA Damage, PROTAC. DC50: 27.0 nM in 24 h. Used for breast cancer research. Patent: WO2025090727A1. Not an FDA-approved drug. The compound is part of a series of protein degraders that offer a new modality for targeting CDK2 in cancer therapy. Appearance: solid powder. Solubility: DMSO 70 mg/mL, ethanol 5 mg/mL. No TFA salt.
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| Molecular Formula |
C23H22F5N5O3
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| Molecular Weight |
511.44
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| Exact Mass |
511.164
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| CAS # |
3083777-50-5
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| Related CAS # |
CDK2 degrader 6; (S)-CDK2 degrader 6
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| PubChem CID |
177805742
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
905
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@@H]1[C@H](CN1C2=CC(=C(C(=C2)F)[C@H]3CCC(=O)NC3=O)F)NC4=NN=C(O4)C56CC(C5)(C6)C(F)(F)F
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| InChi Key |
DYUMYEGVQNMNAQ-HXDJBORHSA-N
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| InChi Code |
InChI=1S/C23H22F5N5O3/c1-10-15(29-20-32-31-19(36-20)21-7-22(8-21,9-21)23(26,27)28)6-33(10)11-4-13(24)17(14(25)5-11)12-2-3-16(34)30-18(12)35/h4-5,10,12,15H,2-3,6-9H2,1H3,(H,29,32)(H,30,34,35)/t10-,12-,15+,21?,22?/m1/s1
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| Chemical Name |
(3R)-3-[2,6-difluoro-4-[(2R,3S)-2-methyl-3-[[5-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-1,3,4-oxadiazol-2-yl]amino]azetidin-1-yl]phenyl]piperidine-2,6-dione
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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. |
| 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 | 1.9553 mL | 9.7763 mL | 19.5526 mL | |
| 5 mM | 0.3911 mL | 1.9553 mL | 3.9105 mL | |
| 10 mM | 0.1955 mL | 0.9776 mL | 1.9553 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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