| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
JH-XI-10-02 targets cyclin-dependent kinase 8 (CDK8), a component of the Mediator complex that regulates transcription. The compound functions as a PROTAC that simultaneously binds to CDK8 and the E3 ubiquitin ligase Cereblon (CRL4Cereblon). This brings CDK8 into proximity with the ubiquitin-proteasome system, leading to its ubiquitination and subsequent proteasomal degradation. JH-XI-10-02 shows no effect on CDK19, demonstrating selectivity for CDK8 over the closely related CDK19.
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| ln Vitro |
JH-XI-10-02 is a bivalent small chemical modifier that activates the E3 ligase CRL4Cereblon, promoting CDK8 ubiquitination and proteosome modification [1]. JH-XI-10-02 (1 μM) causes partial CDK8 degradation in Jurkat cells after 6 hours of treatment. JH-XI-10-02 (1 μM) leads to considerable degradation of CDK8 after 24 hours of treatment [1]. JH-XI-10-02 causes CDK8 degradation in WT Molt4 cells at 5 μM. CRBN nuLl Molt4 cells do not degrade at any concentration (0.1-5 μM) of WT Molt4 cells or CRBN-added Molt4 cells after 24 hours of CRISPER/CAS9-mediated hybridization [1].
In vitro, JH-XI-10-02 is a highly potent and selective PROTAC-based CDK8 degrader with an IC₅0 of 159 nM. It causes proteasomal degradation of CDK8 without affecting CDK8 mRNA levels, indicating that its mechanism is post-translational. JH-XI-10-02 (1 microM) induces significant proteasome-dependent degradation of CDK8 in Jurkat cells after 24 hours, with no significant effect on CDK19 levels. This selective degradation makes it a valuable tool for studying CDK8 biology. |
| ln Vivo |
In vivo studies of JH-XI-10-02 are limited, as it is primarily used as a research tool in cell-based assays. However, given its potent and selective CDK8 degradation activity with an IC₅0 of 159 nM, the compound may have potential for in vivo efficacy studies in animal models of diseases where CDK8 plays a role, such as cancer and inflammatory diseases. Further studies are needed to evaluate its pharmacokinetic properties, bioavailability, and efficacy in vivo. The compound's PROTAC mechanism may enable catalytic degradation.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, JH-XI-10-02 can be evaluated using binding studies to confirm its interaction with CDK8 and Cereblon. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used to measure binding affinities. The compound's ability to induce ternary complex formation between CDK8 and Cereblon can be assessed using biophysical methods such as AlphaScreen or TR-FRET. Ubiquitination assays can be used to measure the compound-induced ubiquitination of CDK8. Standard assay conditions include physiological buffer systems with appropriate pH and ionic strength.
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| Cell Assay |
Blot analysis[1]
Cell Types: Jurkat cells Tested Concentrations: 1 μM Incubation Duration: 6 hrs (hours) and 24 hrs (hours) Experimental Results: CDK8 was partially degraded after 6 hrs (hours) of treatment at 1 μM concentration. CDK8 was Dramatically degraded after 24 hrs (hours) of treatment at 1 μM concentration. Western Blot Analysis [1] Cell Types: WT Molt4 and CRBN null Molt4 cell Tested Concentrations: 0.1, 0.5, 1, 2, 5 μM Incubation Duration: 24 hrs (hours) Experimental Results: CDK8 at 5 μM was degraded in WT Molt4 cells. CRBN null Molt4 cells were not degraded at any concentration. For in vitro cellular experiments, JH-XI-10-02 is tested in cell lines expressing CDK8, such as Jurkat cells. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from nanomolar to micromolar). CDK8 protein levels are assessed by Western blotting or immunofluorescence to determine the extent of degradation. The kinetics and dose-dependence of degradation are characterized. CDK19 levels are monitored to confirm selectivity. Cell viability, proliferation, and downstream transcriptional effects are evaluated using standard assays. |
| Animal Protocol |
For in vivo animal experiments, JH-XI-10-02 can be administered to mice via various routes including intraperitoneal injection or intravenous injection, depending on its solubility and pharmacokinetic properties. The compound's efficacy can be evaluated in xenograft models or other relevant disease models where CDK8 plays a role. Typical dosing regimens may range from 1 to 50 mg/kg. CDK8 protein levels in tissues are assessed by Western blotting or immunohistochemistry. Pharmacodynamic markers and physiological parameters are measured. Tumor volume, body weight, and overall health are monitored.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of JH-XI-10-02 are not extensively detailed in the public literature. As a PROTAC molecule with a molecular weight of 920.14, it may have limited oral bioavailability and may require parenteral administration for in vivo studies. The compound's solubility and stability in biological fluids would influence its pharmacokinetic profile. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies. Formulation development may be necessary for optimal in vivo administration.
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| Toxicity/Toxicokinetics |
Toxicological data for JH-XI-10-02 are limited, as it is primarily a research tool. As a CDK8 degrader, its toxicity would depend on the importance of CDK8 for normal cellular function. CDK8 is a transcriptional regulator involved in various cellular processes, and its degradation could have significant effects on gene expression. Comprehensive toxicology studies including acute and repeated-dose toxicity, genotoxicity, and cardiotoxicity assessments would be needed for further development. Appropriate safety precautions should be taken when handling this compound.
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| References | |
| Additional Infomation |
JH-XI-10-02 is a research compound used for targeted protein degradation studies. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound is a highly potent and selective PROTAC CDK8 degrader with an IC₅0 of 159 nM. It efficiently promotes CDK8 ubiquitination and proteasomal degradation without affecting CDK8 mRNA levels and shows no effect on CDK19.
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| Molecular Formula |
C53H69N5O9
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|---|---|
| Molecular Weight |
920.1430747509
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| Exact Mass |
919.509
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| CAS # |
2209085-22-1
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| PubChem CID |
133081965
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| Appearance |
Yellow to brown solid powder
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| LogP |
7.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
67
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| Complexity |
1770
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| Defined Atom Stereocenter Count |
6
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| SMILES |
O=C(CCOCCOCCOCCOCCNC1=CC=CC2C(N(C(C=21)=O)C1C(NC(CC1)=O)=O)=O)N(C)C1CC[C@@]2(C)[C@@H](C1)CC[C@@H]1[C@H]3CCC(C4=CC=C5C=CN=CC5=C4)[C@@]3(C)CC[C@@H]12
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| InChi Key |
JECHBTRAPARMGI-KMIZWFMDSA-N
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| InChi Code |
InChI=1S/C53H69N5O9/c1-52-19-15-38(32-37(52)9-10-39-42-12-11-41(53(42,2)20-16-43(39)52)35-8-7-34-17-21-54-33-36(34)31-35)57(3)47(60)18-23-64-25-27-66-29-30-67-28-26-65-24-22-55-44-6-4-5-40-48(44)51(63)58(50(40)62)45-13-14-46(59)56-49(45)61/h4-8,17,21,31,33,37-39,41-43,45,55H,9-16,18-20,22-30,32H2,1-3H3,(H,56,59,61)/t37?,38-,39-,41+,42-,43?,45?,52-,53+/m0/s1
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| Chemical Name |
3-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-N-[(3S,8R,10S,13S,14S,17S)-17-isoquinolin-7-yl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]-N-methylpropanamide
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| Synonyms |
JH-XI-10-02JH-XI 10-02JHXI-10-02
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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 : ~100 mg/mL (~108.68 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.75 mg/mL (6.25 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 57.5 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 | 1.0868 mL | 5.4340 mL | 10.8679 mL | |
| 5 mM | 0.2174 mL | 1.0868 mL | 2.1736 mL | |
| 10 mM | 0.1087 mL | 0.5434 mL | 1.0868 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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