| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
BRD4[1]
BRD4 (Bromodomain-containing protein 4) and VHL (von Hippel-Lindau E3 ubiquitin ligase). PROTAC BRD4 Degrader-9 simultaneously binds to BRD4 (a chromatin reader essential for oncogene transcription) and VHL (an E3 ligase), leading to ubiquitination of BRD4 and its subsequent proteasomal degradation. This targeted degradation approach eliminates the entire BRD4 protein rather than merely inhibiting its bromodomain function. |
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| ln Vitro |
PROTAC BRD4 Degrader-9 can be conjugated with STEAP1 and CLL1 antibodies to degrade the BRD4 protein in PC3 prostate cancer cells, with DC50 values of 0.86 nM (STEAP1 conjugate) and 7.6 nM (CLL1 conjugate), indicating sub-nanomolar to low-nanomolar potency for targeted degradation. The compound is a potent PROTAC consisting of a VHL ligand linked to a BRD4 ligand.
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| ln Vivo |
No specific in vivo activity data has been reported. As a targeted protein degrader, the BRD4 Degrader-9-antibody conjugates are expected to demonstrate antitumor efficacy in xenograft models of prostate cancer and other BRD4-driven malignancies. In vivo validation would assess tumor growth inhibition, BRD4 target engagement (by Western blot), and pharmacodynamic markers.
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| Enzyme Assay |
PROTAC BRD4 Degrader-9 is a potent PROTAC. For cell-free assays to assess ternary complex formation, purified VHL and BRD4 proteins are incubated with varying concentrations of PROTAC BRD4 Degrader-9 (0.1 nM-10 uM) in Tris-HCl buffer (pH 7.5) containing 5% DMSO, 150 mM NaCl, 1 mM TCEP, and 0.01% Tween-20. After incubation for 1-2 hours at 4degC, the formation of the VHL-PROTAC-BRD4 ternary complex can be detected by size-exclusion chromatography or by AlphaLISA/TR-FRET assays using labeled proteins. DC50 values are derived from degradation curves.
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| Cell Assay |
For in vitro cellular studies, PC3 human prostate cancer cells (2×10⁵ cells/well) are seeded in 6-well plates and treated with PROTAC BRD4 Degrader-9 (0.1 nM-1 uM) for 6-24 hours. Cells are harvested, lysed, and BRD4 protein levels are quantified by Western blotting using anti-BRD4 antibody. GAPDH or beta-actin serves as a loading control. The concentration at which 50% of BRD4 protein is degraded (DC50) is calculated. To assess catalytic activity, a washout experiment is performed: cells are treated for 4-6 hours, washed extensively, and then incubated in fresh media for an additional 18-24 hours. BRD4 degradation is measured to determine if it persists after compound removal.
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| Animal Protocol |
No in vivo animal study protocols are documented for this specific PROTAC. For testing STEAP1 or CLL1 antibody conjugates, a typical protocol would involve establishing subcutaneous PC3 tumor xenografts in 6-8 week old male NSG mice. When tumors reach 100-150 mm3, the antibody-PROTAC conjugate (e.g., anti-STEAP1-PROTAC BRD4 Degrader-9) is administered intravenously at 1-10 mg/kg, once weekly for 3-4 weeks. Tumor volume is measured twice weekly. Tumors are harvested for BRD4 IHC and TUNEL staining. Body weight and serum markers are monitored.
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| ADME/Pharmacokinetics |
No pharmacokinetic data has been reported for PROTAC BRD4 Degrader-9. The molecular weight of the PROTAC alone is 1312.5 g/mol, which exceeds the typical Lipinski Rule-of-Five limit for oral bioavailability. Therefore, the PROTAC is likely administered via conjugation to antibodies or via injection. Antibody-conjugated PROTACs have a long plasma half-life (days to weeks) due to the antibody-mediated PK.
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| Toxicity/Toxicokinetics |
No toxicity data has been reported. The compound is a research chemical for targeted protein degradation. Potential toxicities may include off-target degradation of other bromodomain-containing proteins or effects on VHL pathway function. As an antibody conjugate, the toxicity profile is determined by the targeting antibody and the degradation of BRD4 in normal tissues.
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| References |
[1]. Dragovich PS, et, al. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy. J Med Chem. 2021 Mar 11;64(5):2576-2607.
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| Additional Infomation |
PROTAC BRD4 Degrader-9 (compound 8a) has the molecular formula C59H71F2N9O15S4 and a molecular weight of 1312.5 g/mol. The compound contains a von Hippel-Lindau (VHL) ligand and a BRD4 ligand connected via a PEG-based linker. BRD4 is an epigenetic reader protein essential for the transcription of oncogenes such as c-MYC. PROTAC technology induces targeted protein degradation (TPD) through the ubiquitin-proteasome pathway.
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| Molecular Formula |
C59H71F2N9O15S4
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|---|---|
| Exact Mass |
1311.392
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| CAS # |
2417370-42-2
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| PubChem CID |
162642588
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| Appearance |
White to off-white solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
22
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| Rotatable Bond Count |
29
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| Heavy Atom Count |
89
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| Complexity |
2750
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)COCCOCCOCCNC(=O)C4=CC5=C(C=C4CS(=O)(=O)C)C6=CN(C(=O)C7=C6C(=CN7)CN5C8=C(C=C(C=N8)F)F)C)OC(=O)OCC(C)(C)SS(=O)(=O)C
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| InChi Key |
YJTABYQWTJXVHI-DEYDXPIJSA-N
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| InChi Code |
InChI=1S/C59H71F2N9O15S4/c1-34-50(86-33-66-34)36-12-10-35(11-13-36)24-65-54(73)46-22-40(85-57(76)84-32-59(5,6)87-89(9,79)80)28-70(46)56(75)51(58(2,3)4)67-47(71)30-83-19-18-82-17-16-81-15-14-62-53(72)41-23-45-42(20-37(41)31-88(8,77)78)43-29-68(7)55(74)49-48(43)38(25-63-49)27-69(45)52-44(61)21-39(60)26-64-52/h10-13,20-21,23,25-26,29,33,40,46,51,63H,14-19,22,24,27-28,30-32H2,1-9H3,(H,62,72)(H,65,73)(H,67,71)/t40-,46+,51-/m1/s1
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| Chemical Name |
[(3R,5S)-1-[(2S)-2-[[2-[2-[2-[2-[[8-(3,5-difluoropyridin-2-yl)-15-methyl-4-(methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-1(16),2(7),3,5,10,13(17)-hexaene-5-carbonyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-5-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-3-yl] (2-methyl-2-methylsulfonylsulfanylpropyl) carbonate
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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) |
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.) |
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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