AZD5438

AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM. It is less potent to CDK5/6 and also inhibits GSK3β. Phase 1.

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AZD5438 Chemical Structure

AZD5438 Chemical Structure
Molecular Weight: 371.46

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

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AZD5438 is available in the following compound libraries:

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Product Information

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  • Research Area

Product Description

Biological Activity

Description AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM. It is less potent to CDK5/6 and also inhibits GSK3β. Phase 1.
Targets CDK2 [1] CDK1 [1] CDK9 [1]
IC50 6 nM 16 nM 20 nM
In vitro 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]
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%. [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]
Features A potent inhibitor of cyclin-dependent kinase (CDK) 1, 2, and 9.

Protocol(Only for Reference)

Kinase Assay: [1]

Recombinant Kinase Assays [1] 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: [1]

Cell lines MCF-7, HCT-116, A549, and IM-9
Concentrations 0 to 10 μM
Incubation Time 48 hours or 72 hours
Method 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.

Animal Study: [1]

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.
Dosages ≤100 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Byth KF, et al. Mol Cancer Ther. 2009, 8(7), 1856-1866.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00088790 Completed Neoplasms AstraZeneca July 2004 Phase 1

Chemical Information

Download AZD5438 SDF
Molecular Weight (MW) 371.46
Formula

C18H21N5O2S

CAS No. 602306-29-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 74 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol 74 mg/mL (199 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-N-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine

Research Area

Customer Reviews (1)


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Rating
Source Helen Sadik from Johhns Hopkins University. AZD5438 purchased from Selleck
Method MTT
Cell Lines MCF10A-Ras,MDA-MB-231, SUM159, MCF-7 cells
Concentrations
Incubation Time 24 h
Results Different breast cancer cell lines were seeded in 96 well plates and treated with different concentrations of AZD5438. After 72h, cell viability was assessed by MTT. Data shows that these cancer cell lines were sensitive to CDK1/2/9 inhibition, however the most aggressive (SUM159 and MDA-MB-231) cells were less susceptible.

Product Citations (2)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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