| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
CDK9/CycT1 13 nM (IC50) CDK9/CycT1(h) 6 nM (IC50) CDK3/CycE(h) 890 nM (IC50) CDK2/CycE(h) 1000 nM (IC50) CDK1/CycB(h) 1100 nM (IC50) CDK5/p35(h) 1600 nM (IC50)
The primary target of Atuveciclib is the cyclin-dependent kinase 9 (CDK9), which is the catalytic subunit of the positive transcription elongation factor b (P-TEFb) complex. P-TEFb is a key regulator of RNA polymerase II (Pol II) during the elongation phase of transcription. It phosphorylates the C-terminal domain (CTD) of Pol II and the negative elongation factor (NELF), allowing Pol II to escape promoter-proximal pausing and proceed with productive elongation. By inhibiting CDK9, Atuveciclib prevents the phosphorylation of these targets, leading to a block in transcriptional elongation. This results in a global suppression of transcription. However, the effect is particularly pronounced on genes with short half-lives, such as the anti-apoptotic protein Mcl-1 and the oncogene MYC. The downregulation of Mcl-1 lowers the apoptotic threshold in cancer cells, making them more susceptible to cell death. The selectivity of Atuveciclib for CDK9 over other CDKs (e.g., 100-fold over CDK2) is crucial for its pharmacological profile. By specifically targeting CDK9, it aims to reduce the side effects associated with pan-CDK inhibitors. This makes it a valuable tool for studying the role of transcriptional regulation in cancer and a promising drug candidate. |
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| ln Vitro |
Positive transcription elongation factor b (PTEFb) is one of four cyclin partners—cyclin T1, cyclin K, cyclin T2a, or cyclin T2b—and a heterodimer of CDK9. Strong antiproliferative action against HeLa cells (IC50=920 nM) and MOLM-13 cells (IC50=310 nM) is demonstrated by atuveciclib (BAY-1143572)[1].
In vitro studies have demonstrated that Atuveciclib is a highly potent and selective inhibitor of CDK9. Its activity is typically measured using kinase assays. In these assays, the CDK9/CycT1 complex is incubated with a peptide substrate and ATP in the presence of varying concentrations of Atuveciclib. The incorporation of phosphate into the substrate is measured, and the IC50 is determined. Atuveciclib inhibits CDK9/CycT1 with an IC50 of 13 nM. Its selectivity is demonstrated by testing it against a panel of other kinases, including CDK2, where it shows a 100-fold selectivity. In cell-based assays, Atuveciclib has been shown to inhibit the phosphorylation of the CTD of RNA polymerase II and to downregulate the expression of short-lived proteins like Mcl-1. This leads to the induction of apoptosis in cancer cell lines. The compound's potency and selectivity make it a valuable tool for studying the role of CDK9 in transcription and cancer biology. These in vitro studies are crucial for characterizing the compound's mechanism of action and for comparing it to other CDK inhibitors. |
| ln Vivo |
Atuveciclib (BAY-1143572) has strong potency and good anticancer activity in in vivo efficacy trials conducted in the MOLM-13 xenograft model in mice. Treatment-to-control (T/C) ratios of 0.64 and 0.49, respectively, (p<0.001), representing dose-dependent antitumor effectiveness, are obtained with daily administration of Atuveciclib (BAY-1143572) at 6.25 or 12.5 mg/kg. In an additional trial, antitumor effectiveness with a T/C ratio of 0.41 and 0.31, respectively, is noted at a higher daily dose of 20 or 25 mg/kg Atuveciclib (BAY-1143572) (p<0.001). The highest amount that naked mice can withstand is 25 mg/kg given once a day. Additionally, T/C ratios of 0.33 and 0.20 (p<0.001) are obtained with Atuveciclib (BAY-1143572) when given at 25 or 35 mg/kg, three days on and two days off. Less than 10% mean body weight loss over the course of the trial indicates that atuveciclib (BAY-1143572) treatment is well-tolerated. Atuveciclib (BAY-1143572) exhibits low blood clearance (CLb 1.1 L/kg per hour) in an in vivo pharmacokinetic investigation in rats[1].
In vivo studies have demonstrated that Atuveciclib is orally bioavailable and has antitumor activity in preclinical models. In xenograft models, where human tumor cells are implanted into immunodeficient mice, oral administration of Atuveciclib has been shown to inhibit tumor growth. The compound's oral bioavailability is a key feature, as it allows for convenient dosing. The mechanism of action in vivo is believed to be the same as in vitro: inhibition of CDK9 leads to the downregulation of Mcl-1 and other survival proteins, inducing apoptosis in tumor cells. The compound's high selectivity for CDK9 over other CDKs is expected to translate into a favorable safety profile. These in vivo studies are essential for validating the therapeutic potential of Atuveciclib and for providing proof-of-concept for CDK9 inhibition as a cancer therapy. The compound has been investigated in clinical trials for the treatment of various cancers, although it may not have progressed to late-stage development. |
| Enzyme Assay |
The in vitro enzyme assay for Atuveciclib is a standard kinase inhibition assay. In this assay, the recombinant CDK9/CycT1 complex is incubated with a peptide substrate (e.g., a fragment of the CTD of RNA polymerase II) and radiolabeled ATP (γ-³²P-ATP) or a fluorescently labeled ATP analog. The reaction is allowed to proceed for a set period, and then the incorporation of phosphate into the substrate is measured. For radiolabeled ATP, the reaction is spotted onto a filter paper, washed, and the radioactivity is measured by scintillation counting. For fluorescent assays, the signal is measured using a plate reader. Atuveciclib is added to the reaction at various concentrations, and the inhibition of kinase activity is measured. The IC50, which is the concentration that inhibits 50% of the kinase activity, is determined from the dose-response curve. For CDK9/CycT1, the IC50 is 13 nM. To test selectivity, the compound is tested against a panel of other kinases, including CDK2, CDK1, CDK4, and CDK6, as well as non-CDK kinases. The selectivity ratio is calculated by comparing the IC50 for CDK9 to the IC50 for the other kinases. These enzyme assays are crucial for characterizing the potency and selectivity of Atuveciclib.
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| Cell Assay |
In vitro cell-based assays for Atuveciclib are used to measure its effects on cancer cell lines. A common assay is the cell viability assay, where cancer cells are seeded in multi-well plates and treated with varying concentrations of Atuveciclib. After 72 hours, cell viability is measured using a reagent like MTT, XTT, or CellTiter-Glo. The IC50 for inhibition of cell growth is determined. To confirm the mechanism of action, cells are treated with Atuveciclib, and the levels of phosphorylated RNA polymerase II (p-RNAPII) and Mcl-1 are measured by Western blotting. A decrease in p-RNAPII and Mcl-1 levels confirms that the compound is inhibiting CDK9 and affecting its downstream targets. Apoptosis is measured using assays like Annexin V staining or caspase-3/7 activation. The selectivity of Atuveciclib can be confirmed by comparing its effects on cancer cells to its effects on normal cells, or by using cells that have been genetically modified to be resistant to CDK9 inhibition. These cell-based assays are essential for validating the compound's mechanism of action and for determining its potency in a cellular context.
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| Animal Protocol |
In vivo animal experiments for Atuveciclib are typically conducted using xenograft models. In a standard protocol, immunodeficient mice are injected subcutaneously with human cancer cells (e.g., from a leukemia, lymphoma, or solid tumor cell line). Once tumors have reached a measurable size, the mice are randomized into treatment groups. Atuveciclib is administered orally (as it is orally bioavailable) at various doses, typically once or twice daily. Tumor growth is monitored by measuring tumor dimensions with calipers. Body weight is also monitored as an indicator of toxicity. At the end of the study, tumors are harvested for analysis of target modulation (e.g., p-RNAPII and Mcl-1 levels by Western blot) and apoptosis (e.g., by TUNEL or cleaved caspase-3 staining). The efficacy is determined by comparing tumor growth inhibition in the treatment groups to the vehicle control group. These in vivo studies are crucial for demonstrating the antitumor activity of Atuveciclib and for providing data for dose selection for clinical trials.
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| ADME/Pharmacokinetics |
Atuveciclib is orally bioavailable, which is a key feature for its development as a therapeutic agent. Its pharmacokinetic (PK) properties have been studied in preclinical species. After oral administration, it is absorbed and distributed throughout the body. Its half-life and clearance determine the dosing frequency. The compound's high selectivity for CDK9 over other kinases is expected to contribute to a favorable PK/PD (pharmacokinetic/pharmacodynamic) relationship. For research use, Atuveciclib is typically supplied as a solid and is soluble in DMSO. Its stability is ensured by storing it under recommended conditions (typically -20°C). A comprehensive PK profile is essential for understanding its in vivo efficacy and for designing dosing regimens for clinical trials. The compound's oral bioavailability makes it a convenient candidate for therapeutic use.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for Atuveciclib is not provided in standard product descriptions. However, its high selectivity for CDK9 over other CDKs (100-fold over CDK2) suggests that it may have a favorable safety profile, as it is less likely to cause off-target effects. The primary on-target toxicity of CDK9 inhibitors is related to their effects on transcription in normal tissues, particularly those with high rates of cell turnover, such as the bone marrow and the gastrointestinal tract. This can lead to myelosuppression (decreased production of blood cells) and gastrointestinal toxicity. However, the selectivity of Atuveciclib may help to reduce these side effects. In preclinical toxicology studies, the compound's safety would be assessed in rodents and dogs to determine its maximum tolerated dose and to identify any target organs of toxicity. Any use in humans would require careful monitoring for side effects.
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| References | |
| Additional Infomation |
Atuveciclib is a positive transcription elongation factor b (P-TEFb) inhibitor. P-TEFb is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T (CycT) and possesses potential antitumor activity. After administration, atuveciclib binds to P-TEFb and inhibits its activity, thereby preventing phosphorylation of its downstream target—the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II)—and inhibiting RNA Pol II-activated transcriptional elongation. This prevents the transcription of pro-tumorigenic genes, induces tumor cell apoptosis, and inhibits tumor cell proliferation. P-TEFb plays a crucial role in gene transcriptional regulation; excessive activation of P-TEFb in cancer cells leads to the transcription of key pro-tumorigenic genes and cancer cell proliferation.
Atuveciclib (BAY-1143572) is a research compound that has been investigated in clinical trials for the treatment of cancer. It is a potent, orally bioavailable, and highly selective inhibitor of CDK9, a key regulator of transcriptional elongation. Its mechanism of action involves inhibiting CDK9, which leads to the suppression of transcription of short-lived anti-apoptotic proteins like Mcl-1, thereby inducing apoptosis in cancer cells. The compound's high selectivity for CDK9 over other CDKs (100-fold over CDK2) is a key feature designed to minimize off-target toxicity. Atuveciclib has demonstrated in vivo efficacy in preclinical tumor models. It represents a promising approach for targeting transcriptional addiction in cancer, a strategy that is being explored for various malignancies. While it may not have progressed to late-stage clinical development, it remains a valuable tool compound for studying CDK9 biology and for validating this target for therapeutic intervention. It is available for research purposes only and is not approved for clinical use. |
| Molecular Formula |
C18H18FN5O2S
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|---|---|
| Molecular Weight |
387.431225299835
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| Exact Mass |
387.116
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| Elemental Analysis |
C, 55.80; H, 4.68; F, 4.90; N, 18.08; O, 8.26; S, 8.27
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| CAS # |
2923012-24-0
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| Related CAS # |
Atuveciclib Racemate;1414943-88-6;Atuveciclib S-Enantiomer;2250279-81-1
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| PubChem CID |
121488167
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| Appearance |
White to off-white solid powder
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| LogP |
4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
27
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| Complexity |
588
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C)(CC1C=CC=C(C=1)NC1N=CN=C(C2C=CC(=CC=2OC)F)N=1)(=N)=O
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| InChi Key |
ACWKGTGIJRCOOM-HHHXNRCGSA-N
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| InChi Code |
InChI=1S/C18H18FN5O2S/c1-26-16-9-13(19)6-7-15(16)17-21-11-22-18(24-17)23-14-5-3-4-12(8-14)10-27(2,20)25/h3-9,11,20H,10H2,1-2H3,(H,21,22,23,24)/t27-/m1/s1
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| Chemical Name |
4-(4-fluoro-2-methoxyphenyl)-N-[3-[(methylsulfonimidoyl)methyl]phenyl]-1,3,5-triazin-2-amine
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| Synonyms |
Atuveciclib; 1414943-94-4; 63Q7F59W0V; BAY1143572; 1,3,5-Triazin-2-amine, 4-(4-fluoro-2-methoxyphenyl)-N-(3-((S-methylsulfonimidoyl)methyl)phenyl)-, (+)-;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 128.5 mg/mL (331.67 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5811 mL | 12.9056 mL | 25.8111 mL | |
| 5 mM | 0.5162 mL | 2.5811 mL | 5.1622 mL | |
| 10 mM | 0.2581 mL | 1.2906 mL | 2.5811 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT02345382
Conditions:LeukemiaLink: https://clinicaltrials.gov/ct2/show/NCT01938638
Conditions:NeoplasmsProducts are for research use only; We do not sell to patients
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