AZD-5153 HNT salt is a 6-hydroxy-2-naphthoic acid salt of AZD-5153. AZD5153 efficiently down-regulates MYC protein levels across the cell line panel irrespective of their sensitivity to AZD5153.
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 treatment markedly impacts transcriptional programs of MYC, E2F and mTOR.
|Cell lines||MV-4-11, MM.1S, and K562 cells|
|Preparation method||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.|
|Incubation time||48 h|
|Animal models||Female CB17 SCID and SCID beige mice|
|Formulation||0.5% hydroxymethylcellulose, 0.1% Tween80 (oral); 20% v/v DMSO/60% v/v HP-B-CD in water (s.c)|
|Administration||by oral gavage mini-pump infusion or s.c|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.
Collins TA, et al. CPT Pharmacometrics Syst Pharmacol. 2017 Jun;6(6):357-364. PMID: 28378926.
Identification of CCR2 and CD180 as Robust Pharmacodynamic Tumor and Blood Biomarkers for Clinical Use with BRD4/BET Inhibitors.
Yeh TC, et al. Clin Cancer Res. 2017 Feb 15;23(4):1025-1035. PMID: 28073847.
AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.
Rhyasen GW, et al. Mol Cancer Ther. 2016 Nov;15(11):2563-2574. PMID: 27573426.
Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).
Bradbury RH, et al. J Med Chem. 2016 Sep 8;59(17):7801-17. PMID: 27528113.
|Related Epigenetic Reader Domain Products|
AZD5153 is a potent bivalent triazolopyridazine based Bromodomain and Extraterminal (BET) Inhibitor, with IC50 value of 5 nM.
MS417 (also known as GTPL7512) is a potent and selective BRD4 inhibitor, which binds to BRD4-BD1 and BRD4-BD2 with IC50s of 30 and 46 nM, respectively.
FL-411 is a selective BRD4 inhibitor.
dBET6 is a highly potent, selective and cell-permeable degrader of BET with an IC50 of 14 nM.
dBET1 is a potent BRD4 protein degrader with an EC50 of 430 nM.
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