AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2-1.7 μM), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. AZD5438 blocks cell cycling at G2-M, S and G1 phases; reduces the proportion of actively cycling cells in vivo. The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.
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Source | Int J Radiat Oncol Biol Phys (2012). Figure 4. AZD5438 |
| Method | Immunoblot analysis | |
| Cell Lines | H1299 cells | |
| Concentrations | 75 nM | |
| Incubation Time | 72 h | |
| Results | Results clearly showed that AZD5438 reduced the frequency of HR by almost 50%. There was also a noticeable decrease in Rad51 expression after treatment with AZD5438 |
| Cell Experiment | |
|---|---|
| Cell lines | MCF-7, MDA-MB-231, HCT-116, HT29, LoVo, SW620, Colo-205 cells line |
| Preparation method | Measurement of Cell Proliferation AZD5438 was tested against solid tumor cell lines as previously described. Briefly, cells were incubated for 48 h with AZD5438 at a range of concentrations. At the end of incubation, the cells were pulsed with 5-bromo-2′-deoxyuridine (BrdUrd) and the amount of DNA synthesis was measured. The IC50 for inhibition of proliferation was specifically determined independently of cell death. Multiple myeloma cell lines were seeded into 96-well plates in RPMI 1640 supplemented with 10% FCS and glutamine and dosed with AZD5438 for 72 h. Cell growth was measured using AlamarBlue (Invitrogen) and GI50 values were calculated with reference to pretreatment control values. |
| Concentrations | 0~10 μ M |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | human HX147 tumor xenografts in Swiss nude (nu/nu genotype; AstraZeneca) mice |
| Formulation | prepared in hydroxy-propyl-methyl-cellulose |
| Dosages | 37.5-75 mg/kg once or twice daily for ~3 wk |
| Administration | oral gavage |
| Molecular Weight | 371.46 |
| Formula | C18H21N5O2S |
| CAS Number | 602306-29-6 |
| Solubility (25°C) | DMSO 64 mg/mL Ethanol 54 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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