Description
AZD5438 can potently inhibit glycogen synthase kinase 3beta cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1,p25-cdk5, cyclin D3-cdk6, and cyclin T-cdk9 with IC50 of 17 nM, 6 nM, 45 nM, 16 nM, 14 nM, 21 nM, and 20 nM.
Storage
2 years at -20 centigrade
Targets
GSK3beta, cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1, cyclin B1-cdk1
Molecular Formula
C18H21N5O2S
Chemical Name
4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-N-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine
Solubility
DSMO 74 mg/mL Water
In vitro
AZD5438 can potently inhibit glycogen synthase kinase 3beta cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1,p25-cdk5, cyclin D3-cdk6, and cyclin T-cdk9 with IC50 of 17 nM, 6 nM, 45 nM, 16 nM, 14 nM, 21 nM, and 20 nM. In SW620 cells, AZD5438 shows inhibition to phosphorylation of the cdk1, cdk2, and cdk4 substrate retinoblastoma and the cdk1 substrates nucleolin and PP1a. AZD5438 also induces cell cycle arrest, for example, AZD5438 induced blocks in G2-M and S phase in MCF-7 cells with concomitant inhibition of DNA synthesis. AZD5438 shows inhibition to a range of tumor cell lines.AZD5438 inhibited MCF-7(Breast), MCF-7AdR(Breast), MDA-MB-231(Breast), HCT-116 (Colon), HCT-15(Colon), HT29(Colon), LoVo(Colon), SW620(Colon), and Colo-205(Colon) with IC50 of 0.22 uM, 0.31uM, 0.46uM, 0.32uM, 1.13uM, 1.05uM, 0.63uM, 0.58uM, and 0.70uM
In vivo
In LoVo xenografts, AZD5438 (100 mg/kg) induce a prolonged inhibition of cells progressing through the cell cycle to G1.In human tumor xenografts including Colo-205, HX147, PC-3, and SW620, AZD5438(75 mg/kg/d) induce 40% inhibition to tumor growth and AZD5438(75 mg/kg/d) can also inhibit tumor growth up to 124% in BT474c model.[1] As a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438 can be a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. In human xenograft animal models in athymic nude mice, treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity. Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G(2)-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis.
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