AZD-5438
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 also been found to potently inhibit the human cyclin E/CDK2 complex, the cyclin B1/CDK1 complex and the cyclin A/CDK2 complex with IC50 of 0.006 μM, 0.016 μM and 0.045 μM respectively. In previous studies, 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:
[1]Camidge DR1, Smethurst D, Growcott J, Barrass NC, Foster JR, Febbraro S, Swaisland H, Hughes A. A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers. Cancer Chemother Pharmacol. 2007 Aug;60(3):391-8. Epub 2006 Nov 18.
[2]Byth KF, Thomas A, Hughes G, Forder C, McGregor A, Geh C, Oakes S, Green C, Walker M, Newcombe N, Green S, Growcott J, Barker A, Wilkinson RW. 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. doi: 10.1158/1535-7163.MCT-08-0836. Epub 2009 Jun 9.
- 1. Kim, Sung O, et al. "The Role of the MEK1/2-ERK-RSK Signalling Axis in Innate Immune Memory." (2023). Electronic Thesis and Dissertation Repository. 9498.
- 2. Rachel Low , Soon-Duck Ha, et al. "Prolonged Inhibition of the MEK1/2-ERK Signaling Axis Primes Interleukin-1 Beta Expression through Histone 3 Lysine 9 Demethylation in Murine?Macrophages." Int J Mol Sci. 2023 Sep 22;24(19):14428. PMID: 37833877
- 3. Cing?z O, Goff SP. "Cyclin-dependent kinase activity is required for type I interferon production." Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):E2950-E2959. PMID:29507205
- 4. Yuan J, Jiang YY, et al. "Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma." Cancer Res. 2017 Dec 1;77(23):6614-6626. PMID:28951465
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 371.46 |
| Cas No. | 602306-29-6 |
| Formula | C18H21N5O2S |
| Synonyms | AZD 5438;AZD5438 |
| Solubility | insoluble in H2O; ≥18.55 mg/mL in DMSO; ≥42.1 mg/mL in EtOH |
| Chemical Name | 4-(2-methyl-3-propan-2-ylimidazol-4-yl)-N-(4-methylsulfonylphenyl)pyrimidin-2-amine |
| SDF | Download SDF |
| Canonical SMILES | CC1=NC=C(N1C(C)C)C2=NC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)C |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
MCF-7 breast cancer cells, |
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Preparation method |
The solubility of this compound in DMSO is >18.6mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
48 h |
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Applications |
AZD5438 induced cell cycle arrest by inhibiting phosphorylation of cdk-dependent substrates, and exhibited the broad antiproliferative activity against asynchronous LoVo, MCF-7 and SW620 tumor cell lines. AZD5438 showed antiproliferative in 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). |
| Animal experiment [1]: | |
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Animal models |
Female nude mice bearing established BT474c, Colo-205, HX147, PC-3, and SW620 human tumor xenografts |
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Dosage form |
Oral gavage, 37.5–75 mg/kg, once or twice daily for 3 wk |
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Application |
In vivo, oral treatment of AZD5438 significantly inhibited 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 inhibited several cell cycle proteins such as, phH3, phosphonucleolin, PP1a, and several phospho-pRb epitopes in a dose-dependent manner. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Byth K F, Thomas A, Hughes G, 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[J]. Molecular cancer therapeutics, 2009, 8(7): 1856-1866. |
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| Description | AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM. | |||||
| Targets | CDK1 | CDK2 | CDK9 | |||
| IC50 | 16 nM | 6 nM | 20 nM | |||
Quality Control & MSDS
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