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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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AZD5438 is a potent inhibitor of CDK1, CDK2 and CDK9 with IC50 of 16 nM, 6 nM, and 20 nM, respectively. |
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Targets
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CDK1 |
CDK2 |
CDK9 |
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IC50 |
16 nM [1] |
6 nM [1] |
20 nM [1] |
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In Vitro
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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. [1] 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). [1] |
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In Vivo
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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%. [1] 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. [1] |
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Clinical Trials
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Study on AZD5438 has been completed in Phase I clinical trials in patients with Advanced Solid Malignancies. |
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Features
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AZD5438 is a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9. |
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Protocol
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Cell Assay
[1]
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| Cell Lines |
MCF-7, HCT-116, A549, and IM-9 |
| Concentrations |
0 to 10 μM |
| Incubation Time |
48 hours or 72 hours |
| Methods |
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. |
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Animal Study
[1]
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| Animal Models |
MCF-7, HCT-116, A549, and IM-9 cells are injected s.c. into the Swiss nude mice and nude rats. |
| Formulation |
AZD5438 is dissolved in hydroxy-propyl-methyl-cellulose. |
| Doses |
≤100 mg/kg |
| Administration |
Administered via p.o. |
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