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| 25mg |
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| 100mg |
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Purity: ≥98%
| Targets |
AZD5153 targets the bromodomain and extraterminal (BET) family of proteins, specifically BRD4. BRD4 is a bromodomain-containing protein that binds to acetylated histones and regulates gene transcription. By simultaneously binding two bromodomains in BRD4, AZD5153 blocks the interaction between BRD4 and acetylated chromatin, thereby inhibiting transcription of oncogenes such as MYC. The compound has an IC50 of 5 nM for BRD4.
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| ln Vitro |
Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. AZD5153 potently disrupts BRD4 foci in U2OS cells with an IC50 value of 1.7 nmol/L. AZD5153 efficiently downregulates MYC protein levels across the cell line panel irrespective of their sensitivity to AZD5153. AML, MM, and DLBCL cell lines are highly sensitive to AZD5153.
Kinase Assay: AZD-5153 HNT salt, the 6-Hydroxy-2-naphthoic acid salt form of AZD5153, is a potent, selective, and orally available BET/BRD4 (bromodomain and extraterminal) bromodomain inhibitor with pKi of 8.3 for BRD4 and possesses a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Cell Assay: Apoptosis was analyzed by flow cytometry using CellEvent Caspase 3/7 Green detection reagent. MV-4-11, MM.1S, and K562 cells were pretreated with AZD5153 or I-BET762 for 48 hours in culture media. Cells were collected and stained with 5 μmol/L final concentration of CellEvent for 30 minutes at 37°C. Flow cytometry was done on a BD Fortessa using the Blue laser and FITC filter set. In vitro, AZD5153 is a potent inhibitor of BRD4 with an IC50 of 5 nM. As a bivalent BET inhibitor, it can simultaneously bind two bromodomains in BRD4, which has been shown to increase antitumor activity compared to monovalent inhibitors. The compound is a reversible inhibitor of BRD4 and has antitumor activity. Specific cellular assay data, such as IC50 values for inhibition of cell proliferation in cancer cell lines, are not detailed in the available sources. |
| ln Vivo |
In vivo administration of AZD5153 leads to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. AZD5153 modulates MYC and HEXIM1 in AML xenograft tumors and human whole blood. AZD5153 is administered orally to mice bearing MV-4-11 xenografts, and pharmacodynamic activity (intratumoral levels of c-Myc) is measured at 2, 4, and 8 h postdose. A considerable decrease in c-Myc expression is observed out to 8 h post dose at free plasma levels of compound<0.2 μM. This decrease in c-Myc expression after treatment with AZD5153 is consistent with other published BET inhibitors
AZD5153 has been shown to increase antitumor activity in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B cell lymphoma. It inhibits hepatocarcinogenesis by altering the BRD4 chromosome landscape and regulating the transcriptome of hepatocellular carcinoma cells. The compound's oral bioavailability supports its use in in vivo efficacy studies. |
| Enzyme Assay |
The BRD4 binding assay for AZD5153 involves incubating the compound with recombinant BRD4 bromodomains (BD1 and BD2) and a fluorescently labeled acetylated histone peptide. The binding affinity is measured using a fluorescence polarization or TR-FRET assay. IC50 values for displacement of the labeled peptide are calculated. The bivalent binding mode can be assessed by surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC).
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| Cell Assay |
To evaluate the cellular activity of AZD5153, cancer cell lines (such as AML, multiple myeloma, or DLBCL cell lines) are seeded in 96-well plates and treated with varying concentrations of AZD5153. Cell proliferation is measured using an MTT or CellTiter-Glo assay after 72 hours of treatment. The IC50 for inhibition of cell proliferation is calculated. BRD4 target gene expression (such as MYC) is measured by quantitative RT-PCR. BRD4 chromatin occupancy can be assessed by ChIP-seq.
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| Animal Protocol |
0.5% hydroxymethylcellulose, 0.1% Tween80 (oral); 20% v/v DMSO/60% v/v HP-B-CD in water (s.c);by oral gavage mini-pump infusion or s.c Female CB17 SCID and SCID beige mice
The in vivo efficacy of AZD5153 is evaluated in xenograft models using human cancer cell lines from acute myeloid leukemia, multiple myeloma, or diffuse large B cell lymphoma. Tumor cells are implanted subcutaneously or orthotopically into immunodeficient mice. When tumors reach a certain size, mice are randomized into treatment groups and administered AZD5153 orally at various doses. Tumor volume and body weight are measured twice weekly. Tumor growth inhibition (TGI) is calculated. Pharmacodynamic markers (such as MYC expression) are measured in tumor tissue. |
| ADME/Pharmacokinetics |
AZD5153 is characterized as being orally available. Specific pharmacokinetic parameters (e.g., Cmax, Tmax, half-life, AUC) are not detailed in the available sources. The compound has a molecular weight of 565.58 and a molecular formula of C30H36ClN7O3. It is a small molecule with properties suitable for oral administration. It is typically stored at -20°C for long-term stability.
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| Toxicity/Toxicokinetics |
Specific toxicity data for AZD5153 are not provided in the available sources. In xenograft studies, the compound demonstrated antitumor activity without mention of overt toxicity. As a research compound, it is intended for laboratory use only and is not approved for human therapeutic applications. Standard safety precautions should be followed when handling this compound.
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| References |
:Mol Cancer Ther.2016 Nov;15(11):2563-2574. Epub 2016 Aug 29.
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| Additional Infomation |
The bivalent BRD4 inhibitor AZD5153 is an orally bioavailable bivalent inhibitor of bromodomain protein 4 (BRD4) with potential antitumor activity. After oral administration, AZD5153 selectively binds to the acetylated lysine recognition motif in both bromodomains of the BRD4 protein, thereby preventing BRD4 from binding to acetylated lysine residues on histones. This disrupts chromatin remodeling and interferes with the expression of target genes, leading to downregulation of certain growth-promoting genes, inducing apoptosis, and inhibiting the proliferation of BRD4-overexpressing tumor cells. BRD4 is a member of the human bromodomain and terminal extra-terminating domain (BET) protein family and is a transcriptional regulator that is overexpressed in some tumor cells and plays an important role in cell proliferation.
AZD5153 is a potent, selective, and orally available inhibitor of the BET family of proteins. It can simultaneously bind two bromodomains in BRD4 with an IC50 of 5 nM. It has been shown to increase antitumor activity in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B cell lymphoma. The compound is used in research related to cancer and transcriptional regulation. |
| Molecular Formula |
C25H33N7O3
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| Molecular Weight |
479.59
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| Exact Mass |
479.264
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| CAS # |
1869912-39-9
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| Related CAS # |
AZD5153 6-Hydroxy-2-naphthoic acid;1869912-40-2
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| PubChem CID |
118693659
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| Appearance |
Light yellow to light brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.668
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| LogP |
2.32
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
699
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1(C)CCN(CCOC2=CC=C(C3CCN(C4=NN5C(OC)=NN=C5C=C4)CC3)C=C2)[C@H](C)C1=O
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| InChi Key |
RSMYFSPOTCDHHJ-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C25H33N7O3/c1-18-24(33)29(2)14-15-30(18)16-17-35-21-6-4-19(5-7-21)20-10-12-31(13-11-20)23-9-8-22-26-27-25(34-3)32(22)28-23/h4-9,18,20H,10-17H2,1-3H3/t18-/m1/s1
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| Chemical Name |
(3R)-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-1,3-dimethylpiperazin-2-one
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| Synonyms |
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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 |
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| 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) |
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0851 mL | 10.4256 mL | 20.8511 mL | |
| 5 mM | 0.4170 mL | 2.0851 mL | 4.1702 mL | |
| 10 mM | 0.2085 mL | 1.0426 mL | 2.0851 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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