Bcr-Abl fusion tyrosine kinase is formed because of a reciprocal chromosomal translocation between chromosomes 9 and 22, producing the Philadelphia chromosome. Bcr-Abl is expressed in chronic myeloid leukemia(CML) and a chronic of acute lymphocytic leukemia[3]. GZD824 is an orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including Bcr-AblWT and Bcr-AblT315I with Kd values of 0.32nM and 0.71nM, respectively, and with IC50 values of 0.34nM and 0.68nM, respectively. In vitro, GZD824 potently suppressed proliferation of Bcr-Abl positive human CML cell lines K562 , Ku812, SUP-B15, U-937, MOLT4 and HL-60 with IC50 values of 0.2nM, 0.13nM, 2.5nM, 390.2nM, 26.3nM, and348.9nM, respectively. GZD824 suppressed the activation of Bcr-Abl and downstream Crk1 and STAT5 in a dose-dependent manner in K562 cells. In vivo, oral administration of GZD824 at 5 and 10mg/kg once daily for 14 consecutive days significantly suppressed tumor growth in mice bearing xenografted K562 cells. Oral administration of GZD824 at 1mg/kg once daily for 14 days induced complete tumor regression in mice bearing xenografted Ku812 cells. In addition, treatment of the mice bearing xenografted Ba/F3 cells expressing Bcr-Abl T315I with GZD824 at dose of 20mg/kg once daily via oral administration for 14 days induced almost complete tumor regression[1].
作用机制
GZD824 inhibits the activation of Bcr-Abl by binding to the ATP-binding site of nonphosphorylated(DGF-out) Bcr-Abl[1].
Olverembatinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
ARK1
0.1 µM
24 hours
Evaluate the effect of GZD824 on cell migration and invasion, results showed GZD824 significantly inhibited the migration and invasion of ARK1 cells
Cancer Med. 2025 Jan;14(1):e70531
Ishikawa
0.1 µM
48 hours
Evaluate the effect of GZD824 on cell migration, results showed GZD824 significantly inhibited the migration of Ishikawa cells
Cancer Med. 2025 Jan;14(1):e70531
NOF
0-100 µM
72 hours
Evaluate the effect of GZD824 on normal cell proliferation, results showed GZD824 had weaker inhibitory effect on NOF cells
Cancer Med. 2025 Jan;14(1):e70531
HPMC
0-100 µM
72 hours
Evaluate the effect of GZD824 on normal cell proliferation, results showed GZD824 had weaker inhibitory effect on HPMC cells
Cancer Med. 2025 Jan;14(1):e70531
E6E7hTERT
0-100 µM
72 hours
Evaluate the effect of GZD824 on normal cell proliferation, results showed GZD824 had weaker inhibitory effect on E6E7hTERT cells
Cancer Med. 2025 Jan;14(1):e70531
KLE
0-100 µM
72 hours
Evaluate the effect of GZD824 on cell proliferation, results showed GZD824 significantly inhibited the proliferation of KLE cells
Cancer Med. 2025 Jan;14(1):e70531
RL95-2
0-100 µM
72 hours
Evaluate the effect of GZD824 on cell proliferation, results showed GZD824 significantly inhibited the proliferation of RL95-2 cells
Cancer Med. 2025 Jan;14(1):e70531
MFE296
0-100 µM
72 hours
Evaluate the effect of GZD824 on cell proliferation, results showed GZD824 significantly inhibited the proliferation of MFE296 cells
Cancer Med. 2025 Jan;14(1):e70531
HEC-1-B
0-100 µM
72 hours
Evaluate the effect of GZD824 on cell proliferation, results showed GZD824 significantly inhibited the proliferation of HEC-1-B cells
Cancer Med. 2025 Jan;14(1):e70531
HEC-1-A
0-100 µM
72 hours
Evaluate the effect of GZD824 on cell proliferation, results showed GZD824 significantly inhibited the proliferation of HEC-1-A cells
Cancer Med. 2025 Jan;14(1):e70531
Olverembatinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD/SCID mice
MV-4-11 subcutaneous xenograft model
Oral
10 or 30 mg/kg
Every other day for 22 consecutive days
HQP1351 significantly suppressed the growth of FLT3-ITD mutant AML xenograft tumors and prolonged the survival of tumor-bearing mice.
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