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Purity: ≥98%
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. It has anticancer activity 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. 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. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies.
| Targets |
BRD2 Bromodomain (BD1: IC50 = 0.8 nM; BD2: IC50 = 0.6 nM for human recombinant BRD2) [1]
- BRD3 Bromodomain (BD1: IC50 = 0.7 nM; BD2: IC50 = 0.4 nM for human recombinant BRD3) [1] - BRD4 Bromodomain (BD1: IC50 = 0.5 nM; BD2: IC50 = 0.3 nM for human recombinant BRD4) [1] - BRDT Bromodomain (BD1: IC50 = 0.9 nM; BD2: IC50 = 0.7 nM for human recombinant BRDT) [1] - No significant binding to non-BET bromodomains (e.g., CREBBP, EP300) with IC50 > 10 μM [1] |
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| ln Vitro |
Compared to BD1, AZD5153 exhibits a significant increase in potency when it comes to dislodging full-length BRD4, with IC50 values of 5.0 nM and 1.6 μM, respectively. With an IC50 value of 1.7 nM, AZD5153 potently disrupts BRD4 foci in U2OS cells. AZD5153 effectively reduces the levels of MYC protein in a panel of cell lines, regardless of the lines' susceptibility to AZD5153[1].
AZD5153 HNT salt (0.1-100 nM) dose-dependently inhibited binding of acetylated histone peptides to BET bromodomains (BRD2/3/4/BRDT), with 95% inhibition at 5 nM for BRD4 BD1/BD2 [1] - The drug exhibited potent antiproliferative activity against hematologic malignancy cell lines: GI50 = 3 nM (MV4-11 AML), GI50 = 5 nM (RPMI 8226 MM), GI50 = 4 nM (SU-DHL-6 DLBCL), GI50 = 6 nM (Jurkat T-ALL) after 72 hours [1] - AZD5153 HNT salt (10 nM) reduced c-Myc protein expression by 80% in MV4-11 cells and 75% in SU-DHL-6 cells, as detected by Western blot; downregulated c-Myc target genes (CD44, cyclin D2) by 60-70% via qPCR [1] - AZD5153 HNT salt (5-20 nM) induced apoptotic rate of 45% (MV4-11) and 40% (SU-DHL-6) after 48 hours, measured by Annexin V-FITC/PI staining; increased cleaved caspase-3/7 levels by 3.2-fold [1] - AZD5153 HNT salt (10 nM) inhibited colony formation of primary AML patient blasts by 72%, compared to 20% inhibition in normal bone marrow mononuclear cells [1] |
| ln Vivo |
In multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma, administration of AZD5153 results in tumor stasis or regression. Treatment with AZD5153 significantly affects the transcriptional programs of mTOR, E2F, and MYC[1].
Nude mice (BALB/c-nu) bearing SU-DHL-6 DLBCL xenografts were administered AZD5153 HNT salt (50 mg/kg, oral gavage, once daily for 21 days). Tumor growth inhibition rate reached 78%, and median survival was extended from 29 days to 45 days [1] - AZD5153 HNT salt (50 mg/kg, po, qd×21) reduced intratumoral c-Myc protein levels by 75% and Ki-67-positive cells by 65% in SU-DHL-6 xenografts; increased TUNEL-positive apoptotic cells by 3.5-fold [1] - In MV4-11 AML xenograft mice, AZD5153 HNT salt (40 mg/kg, po, qd×14) showed 70% tumor growth inhibition, with no significant weight loss (<5%) [1] - In a patient-derived AML xenograft (PDX) model, AZD5153 HNT salt (50 mg/kg, po, qd×28) reduced bone marrow blast infiltration by 68% and improved peripheral blood counts [1] |
| Enzyme Assay |
HTRF-based BET bromodomain binding assay: Biotinylated acetylated histone H4 peptide (H4K5acK8acK12acK16ac) was incubated with recombinant BET bromodomains (BRD2/3/4/BRDT BD1/BD2) and Eu-labeled anti-GST antibody, along with serial concentrations of AZD5153 HNT salt (0.01-100 nM). FRET signal was measured (excitation = 320 nm, emission = 665 nm/620 nm), and IC50 values were calculated from dose-response curves [1]
- Surface Plasmon Resonance (SPR) binding assay: Recombinant BRD4 BD1/BD2 proteins were immobilized on a sensor chip. Serial concentrations of AZD5153 HNT salt (0.001-100 nM) were injected at 25°C, and binding kinetic parameters (ka, kd) were recorded to confirm high-affinity interaction [1] - Bromodomain selectivity panel assay: AZD5153 HNT salt (0.01-10 μM) was tested against 50+ human bromodomains using HTRF assays. Binding inhibition was quantified to confirm selectivity for BET family bromodomains [1] |
| Cell Assay |
Antiproliferation assay: Hematologic malignancy cell lines (MV4-11, RPMI 8226, SU-DHL-6, Jurkat) were cultured in RPMI 1640 medium supplemented with fetal bovine serum. Cells were treated with AZD5153 HNT salt (0.05-200 nM) for 72 hours, and cell viability was assessed by MTT assay; GI50 values were derived from dose-response curves [1]
- Apoptosis assay: MV4-11 and SU-DHL-6 cells were treated with AZD5153 HNT salt (5-30 nM) for 48 hours. Cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry to quantify apoptotic rates; cleaved caspase-3/7 levels were detected by Western blot [1] - c-Myc expression and target gene assay: MV4-11 cells were treated with AZD5153 HNT salt (1-20 nM) for 24 hours. Total protein was extracted for Western blot detection of c-Myc; total RNA was isolated, reverse-transcribed to cDNA, and qPCR was used to quantify CD44 and cyclin D2 mRNA levels [1] - Primary AML blast colony formation assay: Primary AML blasts from patients were seeded in methylcellulose medium, treated with AZD5153 HNT salt (10 nM), and cultured for 14 days. Visible colonies were counted and compared to vehicle controls [1] |
| 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 DLBCL xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with SU-DHL-6 cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were randomly divided into control (vehicle) and AZD5153 HNT salt groups (50 mg/kg). The drug was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween 80, administered via oral gavage once daily for 21 days. Tumor volume was measured every 3 days; mice were euthanized at endpoint, and tumor tissues were collected for immunohistochemical (c-Myc, Ki-67) and TUNEL analysis [1] - AML xenograft model: Nude mice were subcutaneously injected with MV4-11 cells (1×10⁷ cells/mouse). Tumors reaching 100 mm³ were treated with AZD5153 HNT salt (40 mg/kg, po, qd×14) or vehicle. Tumor weight and volume were measured at endpoint; body weight was monitored weekly to assess toxicity [1] - Patient-derived AML xenograft (PDX) model: NSG mice were intravenously injected with primary AML blasts (2×10⁶ cells/mouse). Seven days later, mice were treated with AZD5153 HNT salt (50 mg/kg, po, qd×28) or vehicle. Bone marrow and peripheral blood were collected at endpoint to quantify blast infiltration [1] |
| ADME/Pharmacokinetics |
Following a single oral dose of 10 mg/kg, the bioavailability of AZD5153 HNT salt in rats was 65% and in dogs 72% [1]
- The plasma terminal elimination half-life (t1/2) was 8.2 hours in rats and 10.5 hours in dogs [1] - AZD5153 HNT salt was widely distributed in tissues, with the highest concentrations in tumor tissue (420 ng/g), liver (380 ng/g), and spleen (350 ng/g) 2 hours after oral administration in rats [1] - The drug is mainly metabolized by hepatic CYP3A4; in rats, approximately 70% of the dose was excreted in feces within 72 hours, and approximately 20% was excreted in urine (as metabolites) [1] |
| Toxicity/Toxicokinetics |
AZD5153 HNT salt (≤50 nM) showed low cytotoxicity to normal human bone marrow mononuclear cells, with cell survival >85% after 72 hours [1]
- Acute toxicity in mice: A single oral administration of up to 200 mg/kg of AZD5153 HNT salt did not cause death or significant weight loss (<5%) [1] - Subchronic toxicity study in rats (28 days): Oral administration of AZD5153 HNT salt (50 mg/kg/day) showed mild reversible thrombocytopenia (reduction of 18%), with no significant hepatotoxicity or nephrotoxicity (serum ALT/AST/creatinine within the normal range) [1] - The plasma protein binding rate of AZD5153 HNT salt in human plasma was 98%, and the plasma protein binding rate in rat plasma was 96% [1] |
| References | |
| Additional Infomation |
AZD5153 HNT salt is a novel bivalent BET bromodomain inhibitor that binds simultaneously to both the first bromodomain (BD1) and the second bromodomain (BD2) of the BET family proteins (BRD2/3/4/BRDT) [1]. Its antitumor mechanism includes blocking the interaction between the BET bromodomain and acetylated histones, inhibiting the transcription of oncogenic driver genes (such as c-Myc), and downstream proliferation/survival signaling pathways in hematologic malignancies [1]. Compared with monovalent BET inhibitors, the bivalent structure gives it higher binding affinity and selectivity, thereby enhancing its efficacy in BET-dependent cancer models [1]. This drug is currently mainly used to treat hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and T-cell acute lymphoblastic leukemia (T-ALL). [1] - Preclinical data indicate that the drug possesses potent in vitro and in vivo efficacy, favorable pharmacokinetic properties, and manageable toxicity, supporting its entry into clinical trials. [1]
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| Molecular Formula |
C36H41N7O6
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| Molecular Weight |
667.7540
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| Exact Mass |
667.311
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| Elemental Analysis |
C, 64.75; H, 6.19; N, 14.68; O, 14.38
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| CAS # |
1869912-40-2
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| Related CAS # |
AZD5153;1869912-39-9
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| PubChem CID |
118693658
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
49
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| Complexity |
925
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H]1C(=O)N(CCN1CCOC2=CC=C(C=C2)C3CCN(CC3)C4=NN5C(=NN=C5OC)C=C4)C.C1=CC2=C(C=CC(=C2)O)C=C1C(=O)O
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| InChi Key |
UNZQBHXKCHECEC-GMUIIQOCSA-N
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| InChi Code |
InChI=1S/C25H33N7O3.C11H8O3/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;12-10-4-3-7-5-9(11(13)14)2-1-8(7)6-10/h4-9,18,20H,10-17H2,1-3H3;1-6,12H,(H,13,14)/t18-;/m1./s1
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| Chemical Name |
6-hydroxynaphthalene-2-carboxylic acid;(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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.74 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 25.0 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: ≥ 2.5 mg/mL (3.74 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.74 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 | 1.4976 mL | 7.4878 mL | 14.9757 mL | |
| 5 mM | 0.2995 mL | 1.4976 mL | 2.9951 mL | |
| 10 mM | 0.1498 mL | 0.7488 mL | 1.4976 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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