Olverembatinib dimesylate (HQP1351)

Catalog No.S7194 Synonyms: GZD824 Dimesylate

For research use only.

Olverembatinib dimesylate (HQP1351, GZD824) 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.

Olverembatinib dimesylate (HQP1351) Chemical Structure

CAS No. 1421783-64-3

Selleck's Olverembatinib dimesylate (HQP1351) has been cited by 6 Publications

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Biological Activity

Description Olverembatinib dimesylate (HQP1351, GZD824) 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] Click to View More Targets
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 Research:[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 Research:[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

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
Saline
For best results, use promptly after mixing.

20 mg/mL

Chemical Information

Molecular Weight 724.77
Formula

C29H27F3N6O.2CH4O3S

CAS No. 1421783-64-3
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CC5=C(NN=C5)N=C4.CS(=O)(=O)O.CS(=O)(=O)O

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04260022 Recruiting Drug: Ascentage Pharma HQP1351 bioavailable inhibitor Leukemia Myeloid Chronic|Myeloid Leukemia|Chronic Myeloid Leukemia|Philadelphia Positive Acute Lymphoblastic Leukemia Ascentage Pharma Group Inc. January 9 2020 Phase 1
NCT03594422 Recruiting Drug: HQP1351 Gastrointestinal Stromal Tumor (GIST)|Solid Tumor Adult Ascentage Pharma Group Inc.|HealthQuest Pharma Inc. July 11 2018 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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