product name AZD5438
Description: AZD5438 is a potent small molecule inhibitor of cyclin-dependent kinase (CDK) 1, 2 and 9 with half maximal inhibitory concentration IC50 of 16 nmol/L, 6 nmol/L and 20 nmol/L respectively. AZD5438 has exhibited significant anti-proliferative activity in a few human tumor cell lines with IC50 ranging from 0.2 μmol/L to 1.7 μmol/L, in which the phosphorylation of a few proteins, including CDK substrates pRb, nucleolin, protein phosphatase 1a and RNA polymerase II COOH-terminal domain, and cell cycling at G2-M, S and G1 phases were inhibited.
References: Mol Cancer Ther. 2009 Jul;8(7):1856-66.
371.46
Formula
C18H21N5O2S
CAS No.
602306-29-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 74 mg/mL (199.2 mM)
Water: <1 mg/mL
Ethanol: 74 mg/mL (199.2 mM)
Solubility (In vivo)
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19406225
| In Vitro |
In vitro activity: AZD5438 exhibits the potent inhibitory effect on activity of cyclin-dependent kinases including cyclin E-cdk2, cyclin A-cdk2, cyclin B1-cdk1, cyclin D3-cdk6, and cyclin T-cdk9 with IC50 of 6 nM, 45 nM, 16 nM, 21 nM, and 20 nM, respectively. Besides, AZD5438 also inhibits the kinase activity of p25-cdk5 and glycogen synthase kinase 3β with IC50 of 14 nM and 17 nM, respectively. AZD5438 induces cell cycle arrest by inhibiting phosphorylation of cdk-dependent substrates, and exhibits the broad antiproliferative activity against a range of tumor cell lines including lung, colorectal, breast, prostate, and hematologic tumors with IC50 ranging from 0.2 μM (MCF-7) to 1.7 μM (ARH-77). Kinase Assay: The ability of AZD5438 to inhibit cdk activity is examined using a scintillation proximity assay with recombinant cdk-cyclin complexes of cyclin-Ecdk2, cdk2-cyclin A, cdk4-cyclin D, and recombinant retinoblastoma substrate (amino acids 792-928) or cdk1-cyclin B1 with a peptide substrate derived from the in vitro p34cdc2 phosphorylation site of histone H1 (biotin-X-Pro-Lys-Thr-Pro-Lys-Lys-Ala-Lys-Lys-Leu). The activity of AZD5438 against recombinant cdk5/p25 (at 2 μM ATP) is determined in a scintillation proximity assay-based assay using peptide substrate (AKKPKTPKKAKKLOH). Inhibition of glycogen synthase kinase 3β activity is determined with scintillation proximity assay based on the use of human purified glycogen synthase kinase 3βenzyme and eukaryotic initiation factor 2B substrate (at 1 μM ATP). AZD5438 is screened against active recombinant human cdk6-cyclin D3, cdk7-cyclin H/MAT1 (cdk activating kinase complex), and cdk9-cyclin T using the kinase selectivity screening service. Cell Assay: AZD5438 is tested against solid tumor cell lines. Briefly, cells are incubated for 48 hours 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 hours. Cell growth is measured using AlamarBlue and GI50 values are calculated with reference to pretreatment control values. |
|---|---|
| In Vivo | In vivo, oral treatment of AZD5438 leads to statistically significant inhibition against the growth of human tumor xenografts derived from a wide range of different cancer types including breast, colon, lung, prostate, and ovarian with maximum TGI ranging from 38% to 153%. In the SW620 xenograft model, AZD5438 causes the inhibition of several cell cycle proteins such as, phH3, phosphonucleolin, PP1a, and several phospho-pRb epitopes in a dose-dependent manner. |
| Animal model | MCF-7, HCT-116, A549, and IM-9 cells are injected s.c. into the Swiss nude mice and nude rats. |
| Formulation & Dosage | Dissolved in hydroxy-propyl-methyl-cellulose; 100 mg/kg; oral gavage |
| References | Mol Cancer Ther. 2009 Jul;8(7):1856-66. |
