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| Targets |
The primary targets of PROTAC BET Degrader-1 are BET (bromodomain and extra-terminal) proteins, including BRD2, BRD3, and BRD4. BET proteins are epigenetic readers that regulate gene expression by binding to acetylated lysines on histones. They play critical roles in cancer by driving the expression of oncogenes. PROTAC BET Degrader-1 functions as a PROTAC molecule that simultaneously binds to BET proteins and the E3 ubiquitin ligase Cereblon. This brings BET proteins into proximity with the ubiquitin-proteasome system, leading to their ubiquitination and subsequent proteasomal degradation. By degrading BET proteins, the compound inhibits downstream transcriptional regulation and tumor cell proliferation.
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| ln Vitro |
RS4;11 cells' BRD2, BRD3, and BRD4 protein levels are reduced by PROTAC BET Degrader-1 (Compound 9), a strong PROTAC-based BET degrader that also passes the IC50 of MOLM-13 cells, which are 4.3 nM and 45.5 nM[1].
In vitro studies demonstrate that PROTAC BET Degrader-1 is a potent BET degrader. It decreases the levels of BRD2, BRD3, and BRD4 proteins in RS4;11 cells at 3-10 nM. The compound inhibits the growth of RS4;11 cells with an IC₅0 of 4.3 nM, and shows activity against MOLM-13 cells with an IC₅0 of 45.5 nM. By degrading BET proteins, the compound suppresses BET-dependent transcriptional programs and exerts antitumor effects. Its potent degradation activity makes it a valuable tool for studying BET protein biology and validating BET proteins as therapeutic targets in cancer. |
| ln Vivo |
In vivo studies of PROTAC BET Degrader-1 are focused on evaluating its antitumor efficacy in animal models of BET-dependent cancers. As a potent BET degrader with an IC₅0 of 4.3 nM in RS4;11 cells, the compound is expected to demonstrate significant tumor growth inhibition in vivo. Its PROTAC mechanism enables catalytic degradation of BET proteins, potentially achieving sustained target suppression with favorable pharmacokinetic properties. Further in vivo studies are needed to fully characterize its efficacy, safety, and pharmacokinetic profile in various cancer models.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, PROTAC BET Degrader-1 can be evaluated using binding studies to confirm its interaction with BET proteins 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 BET proteins 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 BET proteins. Standard assay conditions include physiological buffer systems with appropriate pH and ionic strength.
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| Cell Assay |
For in vitro cellular experiments, PROTAC BET Degrader-1 is tested in cell lines such as RS4;11 and MOLM-13 to evaluate its degradation efficacy and anti-proliferative effects. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from nanomolar to micromolar). BET protein levels (BRD2, BRD3, BRD4) are assessed by Western blotting or immunofluorescence. The kinetics and dose-dependence of degradation are characterized. Cell viability and proliferation are assessed using standard assays such as MTT or CellTiter-Glo. Gene expression changes are analyzed by qPCR or RNA sequencing to confirm suppression of BET-dependent transcriptional programs.
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| Animal Protocol |
For in vivo animal experiments, PROTAC BET Degrader-1 can be administered to tumor-bearing mice via various routes including intravenous injection or intraperitoneal injection, depending on its solubility and pharmacokinetic properties. Xenograft models using BET-dependent cancer cell lines such as RS4;11 are commonly used. Typical dosing regimens may range from 1 to 50 mg/kg administered daily or intermittently. Tumor volume is measured regularly, and tumor growth inhibition is calculated. BET protein levels in tumors are assessed by immunohistochemistry or Western blotting. Pharmacodynamic markers and gene expression changes are measured. Body weight and overall health are monitored.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of PROTAC BET Degrader-1 are not extensively detailed in the public literature. As a PROTAC molecule with a molecular weight of 871.90 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 PROTAC BET Degrader-1 are limited, as it is primarily a research tool. As a BET protein degrader, its toxicity would depend on the importance of BET proteins for normal cellular function. BET proteins are key epigenetic regulators involved in gene expression, and their degradation could have significant effects on normal tissues. 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.
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| References | |
| Additional Infomation |
PROTAC BET Degrader-1 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 potent BET degrader that decreases BRD2, BRD3, and BRD4 protein levels at low concentrations. It inhibits RS4;11 cell growth with an IC₅0 of 4.3 nM and MOLM-13 cells with an IC₅0 of 45.5 nM. It recruits Cereblon to promote BET ubiquitination and degradation.
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| Molecular Formula |
C44H45N11O9
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| Molecular Weight |
871.89640879631
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| Exact Mass |
871.34
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| CAS # |
2093386-22-0
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| PubChem CID |
134691733
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
64
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| Complexity |
1770
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1C2=C(C=C(OC)C(C3=C(C)ON=C3C)=C2)C2=C(NC3N(CC)N=C(C4CC4)C=3)N=C(C(NCCCCNC(COC3=CC=CC4=C3C(=O)N(C3CCC(=O)NC3=O)C4=O)=O)=O)N=C12
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| InChi Key |
TXLUZGFDBDQACL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C44H45N11O9/c1-5-54-32(19-27(52-54)23-11-12-23)48-39-37-25-18-31(62-4)26(35-21(2)53-64-22(35)3)17-28(25)47-38(37)50-40(51-39)42(59)46-16-7-6-15-45-34(57)20-63-30-10-8-9-24-36(30)44(61)55(43(24)60)29-13-14-33(56)49-41(29)58/h8-10,17-19,23,29H,5-7,11-16,20H2,1-4H3,(H,45,57)(H,46,59)(H,49,56,58)(H2,47,48,50,51)
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| Chemical Name |
4-[(5-cyclopropyl-2-ethylpyrazol-3-yl)amino]-7-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]butyl]-6-methoxy-9H-pyrimido[4,5-b]indole-2-carboxamide
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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 : ≥ 50 mg/mL (~57.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (1.92 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 16.7 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: ≥ 1.67 mg/mL (1.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1469 mL | 5.7346 mL | 11.4692 mL | |
| 5 mM | 0.2294 mL | 1.1469 mL | 2.2938 mL | |
| 10 mM | 0.1147 mL | 0.5735 mL | 1.1469 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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