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| ln Vitro |
Compound 28 (ITK degrader 1) (0.001-3 μM; 12 hours) dose-dependently lowers the levels of ITK protein in Jurkat cells [1].
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| ln Vivo |
Compound 28, also known as ITK degrader 1, significantly reduced the amount of ITK protein at 2, 8, and 16 hours following treatment of the mice (20 mg/kg; i.p.; single dose). ITK degrader 1 (25 mg/kg; intraperitoneal injection; single dosage) similarly suppressed IL-2 secretion after 6 hours of therapy in an anti-CD3 monoclonal antibody (mAb)-induced IL-2 mouse model [1].. Balb/c mouse pharmacokinetic analysis [1] Path Dosage (g/kg) AUC0-t (ng·h/mL) AUC0-∞ (ng·h/mL) T1/2 (hour) Vz = L/kg Cl (mL/min/kg) Cmax in ng/mL MRTlast (hour) Bioavailability percentage (%) IVP 10 25931 27261 5.75 3055 6.1 3423 5.84 88.4% / iv 5 15138 15415 4.39 2057 5.4 4910 4.42 Mouse Models: Balb/c mice and the IL-2 mouse model triggered by anti-CD3 mAb[1] 20 mg/kg or 25 mg/kg is the dosage. Administration: one dosage; IP Result: When administered at a dose of 20 mg/kg to Balb/c mice, the drug was effectively transported to the peripheral blood and splenic tissue, causing effective, quick, and extended ITK degradation that began at 2 hours and continued for at least 16 hours. effectively reduced the cytokine IL-2 production, with a reduction of more than 70% when compared to the vehicle group at a dose of 25 mg/kg.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Jurkat cells Tested Concentrations: 0.001 μM, 0.003 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM Incubation Duration: 12 h Experimental Results: demonstrated strong ITK degradation potencies in a dose-dependent manner. Even rapidly led to significant ITK protein downregulation after 1 h incubation. |
| Animal Protocol |
Animal/Disease Models: balb/c (Bagg ALBino) mouse, and anti-CD3 mAb-induced IL-2 mouse model[1]
Doses: 20 mg/kg, 25 mg/kg Route of Administration: IP; singel dose Experimental Results: Successfully delivered to the peripheral blood and spleen tissue, eliciting efficient, rapid, and prolonged ITK degradation starting at 2 h and lasting for at least 16 h with 20 mg/kg dose in balb/c (Bagg ALBino) mouse. Efficiently suppressed the production of cytokine IL-2, resulting in a reduction of over 70% compared to the vehicle group with 25 mg/kg dose. |
| References |
[1]. Zhou D, et al. Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with In Vivo Activity. J Med Chem. 2023 Apr 13;66(7):4979-4998.
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| Molecular Formula |
C48H57F3N10O7
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| Molecular Weight |
943.02
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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.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0604 mL | 5.3021 mL | 10.6042 mL | |
| 5 mM | 0.2121 mL | 1.0604 mL | 2.1208 mL | |
| 10 mM | 0.1060 mL | 0.5302 mL | 1.0604 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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