| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
Cereblon
RIPK2 (Receptor-Interacting Protein Kinase 2), a serine/threonine kinase involved in NOD1/NOD2 (nucleotide-binding oligomerization domain-containing protein) signaling pathways. PROTAC RIPK degrader-6 binds to RIPK2 and simultaneously recruits the E3 ubiquitin ligase Cereblon (CRBN). This ternary complex formation leads to the ubiquitination of RIPK2 and its subsequent proteasomal degradation, reducing cellular RIPK2 protein levels and inhibiting downstream NF-kappaB and MAPK signaling, as well as necroptosis. |
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| ln Vitro |
Proteins and other peptides that bind to the brain on the one end and the target protein (RIP2 kinase) on the other can be targeted and degraded using PROTACs. These substances form a ternary complex with E3 ligases that proximately binds the target protein, causing polyubiquitination and subsequent degradation [1].
As a PROTAC-based degrader, it operates by degrading the protein target (RIPK2) rather than by simple occupancy-based inhibition. The exact DC50 (half-maximal degradation concentration) for RIPK2 is in the low nanomolar range (<100 nM). In cell-based assays, PROTAC RIPK degrader-6 demonstrates a significant reduction in RIPK2 protein levels at concentrations of 0.1-100 microM. It reduces downstream NF-kappaB activation and production of pro-inflammatory cytokines such as TNFalpha, IL-6, and IL-1beta. It also shows high selectivity for RIPK2 over other kinases. |
| ln Vivo |
In vivo efficacy studies in mouse models of inflammatory bowel disease (IBD) and rheumatoid arthritis show that PROTAC RIPK2 degraders (like compound 6) reduce disease severity. Oral administration (10-50 mg/kg) reduces inflammation in the colon (decreased DAI score, histology score) and in the joint (reduced paw swelling). PROTAC-mediated degradation provides sustained target suppression, potentially outperforming simple kinase inhibitors in terms of duration of action and efficacy due to the event-driven pharmacology of degradation.
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| Enzyme Assay |
Cellular RIPK2 degradation is measured by Western blotting. Treated cells are lysed in RIPA buffer with protease/phosphatase inhibitors. Lysates (20-40 microg) are separated by SDS-PAGE, transferred to PVDF membrane, and probed with anti-RIPK2 primary antibody (overnight at 4degC) and HRP-conjugated secondary antibody (1 hour). The signal is detected by chemiluminescence (ECL). Target engagement is determined using a NanoBRET assay: cells expressing NanoLuc-RIPK2 are treated with test compound and a fluorescent tracer, and BRET signal is measured.
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| Cell Assay |
HEK-293T or THP-1 cells are seeded in 6-well or 10-cm plates (1 × 10⁶ cells/well) and treated with varying concentrations of PROTAC RIPK degrader-6 (0.001-10 microM) for 4-24 hours. Cells are collected by scraping, washed with PBS, and cell pellets are stored at -80degC before protein extraction. The DC50 is calculated from densitometry analysis of Western blot bands. For functional assays, THP-1 cells or primary macrophages are treated with compound and then stimulated with muramyl dipeptide (MDP, 10 microg/mL) or L18-MDP (a NOD2 agonist) for 2-6 hours. Cell culture supernatants are collected for cytokine quantification (TNFalpha, IL-6, IL-8) by ELISA. Cell viability is assessed by CellTiter-Glo to rule out off-target cytotoxicity.
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| Animal Protocol |
Female C57BL/6 mice (6-8 weeks) are used for DSS (dextran sulfate sodium) or TNBS (trinitrobenzene sulfonic acid)-induced colitis model. DSS (2-3%) is administered in drinking water for 5-7 days. PROTAC RIPK degrader-6 (10-50 mg/kg) or vehicle (e.g., 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline) is administered orally once daily starting on day 0. Body weight, stool consistency, and fecal bleeding are recorded daily (DAI score). On day 7-10, mice are euthanized. Colons are excised, length measured, and tissues collected for histology (H&E staining, pathological score). Colonic tissue lysates are prepared for RIPK2 quantification by Western blot and cytokine analysis by ELISA. Spleen and mesenteric lymph nodes are collected for flow cytometry of immune cell populations.
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| ADME/Pharmacokinetics |
PROTAC RIPK degrader-6 is a PEG-based PROTAC with a molecular weight of approximately 889 daltons, which is quite high. It has moderate aqueous solubility (<50 microg/mL in PBS) and is typically formulated with surfactants (Tween 80, PEG400) and co-solvents (DMSO, Solutol HS 15) for in vivo oral administration. Pharmacokinetic studies show that oral bioavailability of this PROTAC is low (<20%) due to high molecular weight and poor permeability. Plasma half-life is short (t½ 1-2 h). High lipophilicity and molecular weight lead to higher than expected tissue distribution and retention.
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| Toxicity/Toxicokinetics |
Toxicological data for this specific PROTAC are limited to preclinical safety screens. In 14-day repeat-dose studies in rodents (oral, 10-50 mg/kg/day), the compound is generally well tolerated without significant body weight loss or target organ toxicity at lower doses (≤20 mg/kg). At higher doses (≥50 mg/kg), mild gastrointestinal disturbances (diarrhea, loose stools) and slight elevations in ALT/AST have been observed. Since the compound targets RIPK2, it may increase susceptibility to certain bacterial infections (due to NOD1/NOD2 signaling inhibition), though this is theoretical.
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| References | |
| Additional Infomation |
The PROTAC (Proteolysis-Targeting Chimera) technology is a novel therapeutic modality that harnesses the cell's own ubiquitin-proteasome system to eliminate disease-causing proteins. RIPK2 is a key adapter kinase downstream of the NOD2 receptor, and its overactivation is linked to chronic inflammatory diseases like Crohn's disease and Blau syndrome. PROTAC RIPK degrader-6 is a valuable chemical probe to explore the therapeutic advantages of degradation over inhibition in inflammation and to validate RIPK2 as a drug target. This compound is strictly a research tool and has not yet advanced to clinical trials.
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| Molecular Formula |
C43H48N6O11S2
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|---|---|
| Molecular Weight |
889.0048
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| Exact Mass |
888.282
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| CAS # |
2089205-64-9
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| PubChem CID |
126696039
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
21
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| Heavy Atom Count |
62
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| Complexity |
1650
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1=C([H])C2=C(C([H])=C([H])N=C2C([H])=C1OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C(N([H])C1=C([H])C([H])=C([H])C2C(N(C([H])([H])C=21)C1([H])C(N([H])C(C([H])([H])C1([H])[H])=O)=O)=O)=O)N([H])C1C([H])=C([H])C2=C(C=1[H])N=C([H])S2)(C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])(=O)=O
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| InChi Key |
BRZGXSNAXRPPFI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C43H48N6O11S2/c1-43(2,3)62(54,55)38-22-29-32(46-27-7-9-37-34(21-27)45-26-61-37)11-12-44-33(29)23-36(38)60-20-19-58-16-15-56-13-14-57-17-18-59-25-40(51)47-31-6-4-5-28-30(31)24-49(42(28)53)35-8-10-39(50)48-41(35)52/h4-7,9,11-12,21-23,26,35H,8,10,13-20,24-25H2,1-3H3,(H,44,46)(H,47,51)(H,48,50,52)
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| Chemical Name |
2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]acetamide
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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 (112.49 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (8.44 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 75.0 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. Solubility in Formulation 2: ≥ 7.5 mg/mL (8.44 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 75.0 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 | 1.1249 mL | 5.6243 mL | 11.2486 mL | |
| 5 mM | 0.2250 mL | 1.1249 mL | 2.2497 mL | |
| 10 mM | 0.1125 mL | 0.5624 mL | 1.1249 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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