Olverembatinib (GZD824) dimesylate

Catalog No.S7194 Batch:S719401

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Technical Data

Formula

C29H27F3N6O.2CH4O3S
Molecular Weight 724.77 CAS No. 1421783-64-3
Solubility (25°C)* In vitro DMSO 100 mg/mL (137.97 mM)
Water 100 mg/mL (137.97 mM)
Ethanol Insoluble
In vivo (Add solvents to the product individually and in order)
Clear solution
Saline
20.0mg/ml Taking the 1 mL working solution as an example, add 20 mg of this product to 1 ml of physiological saline (0.9% NaCL solution), mix evenly to make it clear, The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description Olverembatinib (GZD824) dimesylate is a novel orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 of 0.34 nM and 0.68 nM, respectively.
Targets
Abl (Q252H) [1] Abl (E255K) [1] Abl (M351T) [1] Abl [1] Abl (H396P) [1] View More
0.15 nM 0.27 nM 0.29 nM 0.34 nM 0.35 nM
In vitro GZD824 potently inhibits the growth of Ba/F3 cells expressing wildtype Bcr-Abl with IC50 of 1.0 nM. Highly consistent with biochemical kinase inhibition and tight protein binding affinity, GZD824 also strongly inhibits the proliferation of Ba/F3 cells expressing Bcr-AblT315I mutant and 14 other resistance-relevant Bcr-Abl mutants. In addition, GZD824 efficiently suppresses the activation of Bcr-Abl as well as downstream Crkl and STAT5 in a concentration-dependent manner in K562 CML cells. [1]
In vivo GZD824, at doses of 5 and 10 mg/kg/day, dose-dependently inhibits the tumor growth in the K562 tumor xenograft and the Ku812 xenograft model without mortality or significant body loss. Besides, GZD824 (20 mg/kg/day) suppresses tumor growth in mice bearing allografted Ba/F3 cells expressing Bcr-AblWT and Bcr-AblT315I. [1]

Protocol (from reference)

Kinase Assay:[1]
  • FRET-Based Z′-Lyte Assay Detecting Peptide Substrate Phosphorylation

    The kinases ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are P3049, PV3864, PV3865, PV3866, and PV3863 are full-length human recombinant protein expressed in insect cells and histidine-tagged. Inhibition activities of inhibitors against Abl1 and its mutants are performed in 384-well plates using the FRET-based Z′-Lyte assay system. Briefly, the kinase substrate is diluted into 5 μL of kinase reaction buffer; and the kinase is added. Compounds (10 nL) with indicated concentrations are then delivered to the reaction by using Echo liquid handler, and the mixture is incubated for 30 min at room temperature. Then 5 μL of 2X ATP solution is added to initiate the reaction, and the mixture is further incubated for 2 h at room temperature. The resulting reactions contains 10 μM (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, T315I) of ATP, 2 μM of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as appropriate. Then, 5 μL of development reagent is added, and the mixture is incubated for 2 h at room temperature before 5 μL of stop solution is added. Fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is examined on an EnVision Multilabel Reader. The data are analyzed using Graphpad Prism5. The data are the mean value of three experiments.
Cell Assay:[1]
  • Cell lines

    Ba/F3 cells expressing wildtype and mutant Bcr-Abl

  • Concentrations

    0-50 μM

  • Incubation Time

    72 hours

  • Method

    Cells in the logarithmic phase are plated in 96-well culture dishes. Twenty-four hours later, cells are treated with the corresponding compounds or vehicle control at the indicated concentration for 72 h. CCK-8 is added into the 96-well plates (10 μL/well) and incubated with the cells for 3 h. OD450 and OD650 are determined by a microplate reader. Absorbance rate (A) for each well is calculated as OD450 – OD650. The cell viability rate for each well is calculated as V% = (As – Ac)/(Ab – Ac) × 100%, and the data were further analyzed using Graphpad Prism5. The data are the mean value of the three experiments. As is the absorbance rate of the test compound well, Ac is the absorbance rate of the well without either cell or test compound, and Ab is the absorbance rate of the well with cell and vehicle control.
Animal Study:[1]
  • Animal Models

    Mice xenograft or allograft tumor models using K562 and transformed Ba/F3 cells expressing native Bcr-Abl or Bcr-Abl mutants.

  • Dosages

    ~20 mg/kg

  • Administration

    oral gavage

Customer Product Validation

, , Oncotarget, 2016, 7(48):79842-79853

Selleck's Olverembatinib (GZD824) dimesylate has been cited by 6 publications

c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis [ Lab Invest, 2021, 10.1038/s41374-021-00683-6] PubMed: 34732849
GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress [ Mol Pharmacol, 2020, 98(6):669-676] PubMed: 33033108
c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis. [ J Leukoc Biol, 2019, 106(2):455-466] PubMed: 30861207
The Lung is a Host Defense Niche for Immediate Neutrophil-Mediated Vascular Protection. [ Sci Immunol, 2017, 2(10)] PubMed: 28626833
PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines. [ Oncotarget, 2017, 8(14):23213-23227] PubMed: 28390196
Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1fusion protein in human Acute Lymphoblastic Leukemia. [Simioni C, et al. Oncotarget, 2016, 7(48):79842-79853] PubMed: 27821800

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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