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AZD-5438

MCE China：AZD-5438

Brand：MedChemExpress (MCE)

Cat. No.HY-10012

CAS：602306-29-6

Purity：99.91%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 1 year -20°C 6 months

Shipping：Room temperature in continental US; may vary elsewhere.

Description：AZD-5438 is a potent CDK1, CDK2, and CDK9 inhibitor, with IC50s of 16 nM, 6 nM, and 20 nM in cell-free assays, respectively. AZD-5438 shows less inhibition activity against GSK3β, CDK5 and CDK6.

In Vitro：AZD5438 potently inhibits the kinase activity of cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1, p25-cdk5, cyclin D3-cdk6, and cyclin T-cdk9 (IC50, 6, 45, 16, 21, and 20 nM, respectively). AZD5438 potently inhibits the kinase activity of cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1, p25-cdk5, cyclin D3-cdk6, and cyclin T-cdk9 (IC50, 6, 45, 16, 21, and 20 nM, respectively). In common with many other cdk inhibitors, AZD5438 also inhibits the kinase activity of p25-cdk5 and glycogen synthase kinase 3β in vitro (IC50, 14 and 17 nM, respectively)[1]. AZD5438 significantly augments cellular radiosensitivity in NSCLC cells. Combined treatment with AZD5438 and irradiation also enhances tumor growth delay, with an enhancement factor ranging from 1.2-1.7[2].

In Vivo：AZD5438 (50 mg/kg twice daily or 75 mg/kg, p.o.) inhibits human tumor xenograft growth. In vivo, AZD5438 reduces the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts shows that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintains suppression of biomarkers, such as phospho-pRbSer249/Thr252, for up to 16 hours following a single oral dose[1].

Animal Administration：All human tumor xenografts except HX147 are established by s.c. injecting 100 μL of tumor cells (between 1×106 and 1×107 cells mixed 1:1 with Matrigel). HX147 tumors are derived from fragment implants (1 mm3 pieces) from tumors taken from mice initially implanted s.c. with 1×107 cells. These tumor fragments are passaged in mice thrice before implant for antitumor work. Tumors are measured up to three times per week with calipers, tumor volumes are calculated, and the data are plotted as geometric mean for each group versus time, as previously described. Animals are randomized into treatment groups (typically n=10) when tumors reach a mean size of approximately >0.2 cm3 and >0.5 cm3 for mice and rats, respectively. AZD5438 is prepared in hydroxy-propyl-methyl-cellulose. Animals are given either AZD5438 (37.5-75 mg/kg) or vehicle control once or twice daily by oral gavage for appr 3 wk in each case. Tumor volume and percentage tumor growth inhibition (% TGI) are calculated as described previously. Statistical analysis of any change in tumor volume is carried out using a standard t test (P

Cell Assay：AZD5438 is tested against solid tumor cell lines as previously described. Briefly, cells are incubated for 48 h with AZD5438 at a range of concentrations. At the end of incubation, the cells are pulsed with 5-bromo-2'-deoxyuridine (BrdUrd) and the amount of DNA synthesis is measured. The IC50 for inhibition of proliferation is specifically determined independently of cell death. Multiple myeloma cell lines are seeded into 96-well plates in RPMI 1640 supplemented with 10% FCS and glutamine and dosed with AZD5438 for 72 h. Cell growth is measured using AlamarBlue and GI50 values are calculated with reference to pretreatment control values.

IC50 & Target：cdk2-cyclin E 6 nM (IC50) cdk2-cyclin A 45 nM (IC50) cdk5-p25 14 nM (IC50) cdk1-cyclin B1 16 nM (IC50) cdk9-cyclin T 20 nM (IC50) cdk6-cyclin D3 21 nM (IC50) cdk4-cyclin D1 449 nM (IC50) cdk7-cyclin H 821 nM (IC50)

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References：

[1]. Byth KF, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther. 2009 Jul;8(7):1856-66. Epub 2009 Jun 9.  [Content Brief]

[2]. Raghavan P, et al. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells. Int J Radiat Oncol Biol Phys. 2012 Jul 12.  [Content Brief]