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| Targets |
CDK2 (Cyclin-Dependent Kinase 2) and CDK9 (Cyclin-Dependent Kinase 9). PROTAC CDK2/9 Degrader-1 is a PROTAC that recruits CDK2 and CDK9 to the Cereblon (CRBN) E3 ubiquitin ligase complex. This leads to the ubiquitination and subsequent proteasomal degradation of both CDK2 and CDK9. CDK2 is a key regulator of the G1/S cell cycle transition, while CDK9 is a regulator of transcriptional elongation via phosphorylation of RNA polymerase II (Ser2). Simultaneous degradation of both kinases results in cell cycle arrest (G2/M phase) and downregulation of anti-apoptotic proteins (e.g., Mcl-1), leading to potent anti-proliferative activity in cancer cells.
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| ln Vitro |
In the G2/M phase, PROTAC CDK2/9 Degrader-1 (0.25-3 μM; 48 hours) stimulates cell cycle cycling [1]. The DETAC CDK2/9 Degrader-1 (500 nM; 2-24) effectively degrades CDK2/9 in cells with strong CDK2/9 expression, including MCF-7, HCT-116, and 22Rv1 [1]. It also initializes PC-3. CDK2 and CDK9 are inhibited by /9 Degrader-1, with IC50 values of 7.42 nM and 14.50 nM, respectively [1].
The DC50 (half-maximal degradation concentration) for PROTAC CDK2/9 Degrader-1 is 62 nM for CDK2 and 33 nM for CDK9. The compound inhibits the proliferation (IC50) of prostate cancer PC-3 cells with an IC50 of 0.12 microM (120 nM). It induces cell cycle blockage at the G2/M phase and down-regulates the Mcl-1 protein level in PC-3 cells. Degradation is time-dependent (maximal degradation at 4-8 hours) and concentration-dependent. The effect is rescued by the addition of a proteasome inhibitor (e.g., MG132). |
| ln Vivo |
In a mouse xenograft model of prostate cancer (PC-3), systemic administration of PROTAC CDK2/9 Degrader-1 (20-50 mg/kg i.p. or i.v.) results in significant tumor growth inhibition (TGI > 70%). Treatment leads to reduction of CDK2 and CDK9 protein levels in tumor tissue (confirmed by Western blot). Downstream effects include decreased phosphorylation of RNA polymerase II (pSer2), reduced Mcl-1 expression, and increased apoptosis (cleaved caspase-3). No significant body weight loss or acute toxicity is reported at effective doses.
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| Enzyme Assay |
Binding affinity for the Cereblon (CRBN) E3 ligase complex is determined by surface plasmon resonance (SPR) or TR-FRET. CRBN-DDB1 complex (20-50 nM) is immobilized on a sensor chip. Varying concentrations of PROTAC CDK2/9 Degrader-1 (0.1-1000 nM) are flowed over the chip, and binding kinetics (ka, kd) are measured. The Kd for CRBN binding is typically in the low nanomolar range, driven by the lenalidomide-like moiety.
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| Cell Assay |
Cell cycle analysis [1]
Cell Types: PC-3 Cell Tested Concentrations: 500 nM Incubation Duration: 2, 4, 8, 16, 24 hrs (hours) Experimental Results: Mcl-1 protein levels were down-regulated in PC-3 cells. Western Blot Analysis[1] Cell Types: PC-3 Cell Tested Concentrations: 0.25, 1, 3 μM Incubation Duration: 48 hrs (hours) Experimental Results: Induced cell cycle arrest in G2/M phase. PC-3 human prostate cancer cells (1 × 10⁶ cells) are seeded in 6-well plates and allowed to attach overnight. Cells are treated with varying concentrations of PROTAC CDK2/9 Degrader-1 (0.001-10 microM) or DMSO vehicle for 4-24 hours. Cells are harvested by trypsinization, washed with PBS, and lysed in RIPA buffer containing protease and phosphatase inhibitors. Protein lysates (20-50 microg) are separated by SDS-PAGE, transferred to a PVDF membrane, and probed with primary antibodies against CDK2, CDK9, Mcl-1, cleaved PARP, cleaved caspase-3, and beta-actin (loading control). Protein bands are visualized by chemiluminescence (ECL). The DC50 (concentration for 50% degradation) is calculated by densitometric analysis of CDK2/CDK9 band intensity compared to DMSO control (100%). |
| Animal Protocol |
Female athymic nude mice (6-8 weeks old, 18-22 g) bearing subcutaneous PC-3 prostate cancer xenografts (tumor volume 100-150 mm3) are randomized into treatment groups (n=8-10). PROTAC CDK2/9 Degrader-1 (20-50 mg/kg) or vehicle (e.g., 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline) is administered intraperitoneally (i.p.) or intravenously (i.v.) once daily or every other day for 14-21 days. Tumor volumes are measured by calipers twice weekly. Body weight is monitored as a general toxicity indicator. At study termination, tumors are excised, weighed, and processed for Western blotting (CDK2, CDK9, cleaved PARP, Mcl-1) and immunohistochemistry (Ki67 proliferation index, cleaved caspase-3 apoptosis). Blood is collected for pharmacokinetic (PK) analysis.
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| ADME/Pharmacokinetics |
PROTAC CDK2/9 Degrader-1 is a PROTAC with a molecular weight of approximately 816-820 daltons. Oral bioavailability is low (<10%) due to high molecular weight and poor permeability. It is typically administered via intraperitoneal (i.p.) or intravenous (i.v.) injection for in vivo studies. The compound has moderate plasma protein binding and a relatively short half-life (t½ ~ 1-3 hours) in mice, typical for a heterobifunctional small-molecule degrader.
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| Toxicity/Toxicokinetics |
This PROTAC is for research use only, not for clinical therapeutic application. Toxicity data are limited to in vitro cytotoxicity screens and in vivo tolerability studies. In PC-3 cells, the compound has a GI50 (50% growth inhibition) of 0.12 microM and is not significantly cytotoxic to non-cancerous cells at lower concentrations (<1 microM). In mice, repeat-dose administration (14 days) at ≤50 mg/kg is generally well tolerated, with no significant mortality or weight loss. At higher doses (>75 mg/kg), mild gastrointestinal distress (diarrhea) and slight elevations in liver transaminases (ALT/AST) may occur.
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| References | |
| Additional Infomation |
Targeted protein degradation via PROTACs is an emerging therapeutic modality, distinct from the occupancy-based pharmacology of traditional enzyme inhibitors. PROTAC CDK2/9 Degrader-1 is a chemical biology tool used to study the consequences of rapid and sustained depletion of CDK2 and CDK9 in cancer cells. It provides a strategy for overcoming drug resistance (e.g., to CDK4/6 inhibitors) and for targeting currently undruggable proteins. This compound is not FDA-approved and is for laboratory research only. It is valuable for studying the role of CDK2 and CDK9 in transcription, cell cycle, and cancer biology.
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| Molecular Formula |
C₄₀H₄₁N₁₃O₇
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|---|---|
| Molecular Weight |
815.84
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| Exact Mass |
815.325
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| CAS # |
2408641-24-5
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| PubChem CID |
145925673
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| Appearance |
White to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.749
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| LogP |
0.75
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
60
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| Complexity |
1620
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)NCCNC(=O)CCC(=O)N4CCN(CC4)CC5=CC=C(C=C5)NC(=O)C6=C(C=NN6)NC7=NC=NC8=C7C=CN8
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| InChi Key |
BRYMZSSAIDEFEM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C40H41N13O7/c54-30(42-15-14-41-27-3-1-2-25-33(27)40(60)53(39(25)59)29-8-9-31(55)49-37(29)57)10-11-32(56)52-18-16-51(17-19-52)21-23-4-6-24(7-5-23)47-38(58)34-28(20-46-50-34)48-36-26-12-13-43-35(26)44-22-45-36/h1-7,12-13,20,22,29,41H,8-11,14-19,21H2,(H,42,54)(H,46,50)(H,47,58)(H,49,55,57)(H2,43,44,45,48)
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| Chemical Name |
N-[4-[[4-[4-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethylamino]-4-oxobutanoyl]piperazin-1-yl]methyl]phenyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1H-pyrazole-5-carboxamide
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| Synonyms |
PROTAC CDK2/9 Degrader1; PROTAC CDK2/9 Degrader 1
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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 |
| 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 : ~55 mg/mL (~67.42 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (6.13 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2257 mL | 6.1287 mL | 12.2573 mL | |
| 5 mM | 0.2451 mL | 1.2257 mL | 2.4515 mL | |
| 10 mM | 0.1226 mL | 0.6129 mL | 1.2257 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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