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.
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.
|Cell lines||Ba/F3 cells expressing wildtype and mutant Bcr-Abl|
|Preparation 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.|
|Incubation time||72 hours|
|Animal models||Mice xenograft or allograft tumor models using K562 and transformed Ba/F3 cells expressing native Bcr-Abl or Bcr-Abl mutants.|
|Formulation||1% DMSO, 22.5% Cremophor, 7.5% ethanol, and 69% normal saline|
|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||100 mg/mL in DMSO|
GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways.
Ye W, et al. Oncotarget. 2016 Jul 28;8(50):87002-87015. PMID: 29152059.
Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia.
Simioni C, et al. Oncotarget. 2016 Nov 29;7(48):79842-79853. PMID: 27821800.
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