GZD 824

Research use only, not for human use.

GZD824 is an orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT, IC50: 0.34 nM) and Bcr-Abl(T315I, IC50: 0.68 nM).

GZD824 is a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. GZD824 tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. GZD824 potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. GZD824 also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.

Western Blot Analysis Cell Line:K562 cells Concentration:1 nM, 2 nM, 5 nM, 10 nM, 20nM Incubation Time:4.0 hours Result:Inhibited Bcr-Abl signaling in K562 cell lines.

Animal Model:SCID nude mice, bearing allografted Ba/F3 cells expressing Bcr-AblT315I Dosage:1 mg/kg, 2 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg Administration:Oral gavage, daily, for 10 days Result:Efficiently prolonged animal survival in an allograft leukemia tumor model.Animal Model:Rats Dosage:5 mg/kg for i.v.; 25 mg/kg for oral (Pharmacokinetic Analysis) Administration:Intravenous injection and oral administrationResult:Oral bioavailability (48.7%), Cmax (390.5 μg/L), T1/2 (5.6 h).

GZD824 | GZD 824 | GZD-824

Endocrinology/Hormones

AChR

Abl (E254K)

Cancer

——

1257628-77-5

532.57

C29H27F3N6O

>98% (HPLC)

DMSO : ≥ 100 mg/mL; 187.77 mM

CN1CCN(Cc2c(cc(NC(=O)c3cc(C#Cc4cc5c([nH]nc5)nc4)c(C)cc3)cc2)C(F)(F)F)CC1

3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

(-20℃)

With Ice Pack

≥ 2 years