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| Targets |
The primary targets of FKBP12 PROTAC dTAG-7 are FKBP12F36V (a mutant form of FKBP12 containing a F36V point mutation) and BET BRD4. The compound functions as a bifunctional degrader by simultaneously binding to the target protein (FKBP12F36V or BRD4) and the E3 ubiquitin ligase cereblon (CRBN). This brings the target protein into proximity with the ubiquitin-proteasome system, leading to its ubiquitination and subsequent proteasomal degradation. dTAG-7 consists of a ligand selective for F36V single-point mutated FKBP12 conjugated to a cereblon ligand by a linker. The compound induces selective degradation of FKBP12F36V in a CRBN-dependent manner in cells.
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| ln Vitro |
In vitro studies have demonstrated that FKBP12 PROTAC dTAG-7 is a potent and selective degrader of FKBP12F36V and BET BRD4. The compound is cell-permeable and induces degradation of its target proteins in a CRBN-dependent manner. In cellular assays, dTAG-7 has been shown to effectively reduce the levels of FKBP12F36V fusion proteins and BRD4, leading to downstream effects on gene expression and cell function. The compound is used as a chemical tool to study the biological functions of FKBP12 and BRD4 and to validate these proteins as therapeutic targets. The dTAG system, of which dTAG-7 is a key component, is a widely used method for inducible protein degradation.
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| ln Vivo |
In vivo studies of FKBP12 PROTAC dTAG-7 are focused on its use as a chemical probe to study protein function in animal models. The compound's ability to selectively degrade FKBP12F36V and BRD4 in vivo makes it a valuable tool for investigating the physiological roles of these proteins. dTAG-7 can be administered to animals to achieve target protein degradation, and the resulting phenotypic effects can be studied. This approach allows for the temporal and reversible control of protein levels, providing insights into protein function that are complementary to genetic knockout approaches. The compound is used in studies of cancer, epigenetics, and other biological processes.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, FKBP12 PROTAC dTAG-7 can be evaluated using binding studies to confirm its interaction with FKBP12F36V and cereblon. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used to measure the binding affinity of the compound for its targets. However, the primary readout for PROTAC activity is target protein degradation, which is typically assessed in cellular assays. The compound's ability to induce ternary complex formation between the target protein and the E3 ligase can be studied using biochemical or biophysical methods. Standard assay conditions include physiological buffer systems with appropriate pH and ionic strength.
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| Cell Assay |
For in vitro cellular experiments, FKBP12 PROTAC dTAG-7 is tested in cell lines expressing FKBP12F36V fusion proteins or BRD4. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from nanomolar to micromolar) for defined periods. Target protein degradation is assessed by Western blotting or immunofluorescence. The kinetics and dose-dependence of degradation are characterized. Downstream effects on cell signaling, gene expression, and cell function are evaluated using qPCR, RNA sequencing, or functional assays. The CRBN-dependence of degradation can be confirmed using CRBN knockout cells or by co-treatment with a CRBN inhibitor. Cytotoxicity and cell viability are monitored.
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| Animal Protocol |
For in vivo animal experiments, FKBP12 PROTAC dTAG-7 can be administered to mice via various routes including intraperitoneal injection or oral gavage. The compound is used in studies where FKBP12F36V fusion proteins or BRD4 are expressed in specific tissues or cell types. Target protein degradation in vivo is confirmed by Western blotting or immunohistochemistry of tissues. Phenotypic effects are assessed using appropriate assays, such as tumor growth measurements in cancer models or behavioral tests in neurological models. Pharmacodynamic markers and physiological parameters are measured to assess compound efficacy. The compound's in vivo activity depends on its pharmacokinetic properties and bioavailability.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of FKBP12 PROTAC dTAG-7 are not extensively detailed in the public literature. As a large molecule with a molecular weight of 1210.32 g/mol, 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. The compound's metabolism and excretion pathways remain to be fully characterized. Formulation development may be necessary for optimal in vivo administration.
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| Toxicity/Toxicokinetics |
Toxicological data for FKBP12 PROTAC dTAG-7 are limited, as it is primarily a research tool. As a PROTAC that induces protein degradation, its toxicity would depend on the importance of its target proteins (FKBP12 and BRD4) for normal cellular function. Degradation of BRD4, which is a key epigenetic regulator, could have significant effects on gene expression and cell viability. Comprehensive toxicology studies would be needed for further development. Appropriate safety precautions should be taken when handling this compound, including the use of personal protective equipment and adherence to institutional safety guidelines for handling PROTACs and other protein degraders.
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| References | |
| Additional Infomation |
FKBP12 PROTAC dTAG-7 is a research compound used for inducible protein degradation in cells and in vivo. 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 first-generation degrader for mutant FKBP12F36V fusion proteins and is a key component of the dTAG system for inducible protein degradation. dTAG-7 selectively degrades FKBP12F36V in a CRBN-dependent manner in cells and also degrades BET BRD4. It is a valuable tool for studying protein function and validating therapeutic targets.
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| Molecular Formula |
C63H79N5O19
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|---|---|
| Molecular Weight |
1210.32347893715
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| Exact Mass |
1209.536
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| CAS # |
2064175-32-0
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| PubChem CID |
131954816
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| Appearance |
White to off-white solid powder
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| LogP |
5.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
19
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| Rotatable Bond Count |
36
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| Heavy Atom Count |
87
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| Complexity |
2200
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O([C@@H](C1=CC=CC=C1OCC(NCCCOCCOCCOCCCNC(COC1=CC=CC2=C1C(N(C2=O)C1C(NC(CC1)=O)=O)=O)=O)=O)CCC1C=CC(=C(C=1)OC)OC)C([C@@H]1CCCCN1C([C@H](C1C=C(C(=C(C=1)OC)OC)OC)CC)=O)=O
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| InChi Key |
IFCAWDLUIZXIPI-FJDAOBEISA-N
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| InChi Code |
InChI=1S/C63H79N5O19/c1-7-42(41-36-52(79-4)58(81-6)53(37-41)80-5)60(73)67-28-11-10-17-46(67)63(76)87-48(23-20-40-21-24-49(77-2)51(35-40)78-3)43-15-8-9-18-47(43)85-38-55(70)64-26-13-29-82-31-33-84-34-32-83-30-14-27-65-56(71)39-86-50-19-12-16-44-57(50)62(75)68(61(44)74)45-22-25-54(69)66-59(45)72/h8-9,12,15-16,18-19,21,24,35-37,42,45-46,48H,7,10-11,13-14,17,20,22-23,25-34,38-39H2,1-6H3,(H,64,70)(H,65,71)(H,66,69,72)/t42-,45?,46-,48+/m0/s1
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| Chemical Name |
[(1R)-3-(3,4-dimethoxyphenyl)-1-[2-[2-[3-[2-[2-[3-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-2-oxoethoxy]phenyl]propyl] (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carboxylate
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~150 mg/mL (~123.93 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 3.75 mg/mL (3.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 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. Solubility in Formulation 2: 3.75 mg/mL (3.10 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 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. View More
Solubility in Formulation 3: ≥ 3.75 mg/mL (3.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8262 mL | 4.1311 mL | 8.2623 mL | |
| 5 mM | 0.1652 mL | 0.8262 mL | 1.6525 mL | |
| 10 mM | 0.0826 mL | 0.4131 mL | 0.8262 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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