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Purity: ≥98%
Atuveciclib (formerly known as BAY-1143572) is novel, potent, oral and highly selective PTEFb/CDK9 inhibitor with antitumor activity. It is more than 100-fold more selective for CDK9 over CDK2, and it inhibits CDK9/CycT1 with an IC50 of 13 nM. With IC50 values of 45 nM for GSK3α and 87 nM for GSK3β, respectively, it also inhibits GSK3 kinase. A Phase I clinical trial for ateveciclib is presently underway. One promising new strategy in cancer therapy is selective inhibition of exclusively transcription-regulating PTEFb/CDK9. The orally available clinical candidate atuveciclib (BAY1143572) was ultimately identified through lead optimization efforts that began with lead compound BAY-958 and strictly focused on kinase selectivity, physicochemical, and DMPK properties. BAY 1143572, which is structurally distinguished by an uncommon benzyl sulfoximine group, demonstrated the best overall profile both in vitro and in vivo, demonstrating good tolerability and high efficacy in mice and rat xenograft models. Among the PTEFb/CDK9 inhibitors in clinical trials for cancer treatment, BAY 1143572 is the most potent and highly selective inhibitor.
Targets |
CDK9 (IC50 = 13 nM); GSK-3α (IC50 = 45 nM); GSK3β (IC50 = 87 nM)
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ln Vitro |
Atuveciclib (BAY-1143572) induces apoptosis and has a median IC50 of 385 nM (range 230-1100 nM), which inhibits the proliferation of seven AML cell lines that are positive and negative for MLL rearrangements[1]. With a minimum of 50-fold selectivity against other CDKs, atuveciclib (BAY-1143572) exhibits strong and highly selective PTEFb-kinase inhibitory activity in the low nanomolar range against PTEFb/CDK9. A panel of non-CDK kinases exhibits good selectivity towards ateveciclib (BAY-1143572). With IC50 values that are sub-micromolar, it exhibits broad antiproliferative activity against a panel of tumor cell lines. Concentration-dependent inhibition of RNA polymerase II phosphorylation is observed, followed by a downstream decrease in MYC mRNA and protein levels[2].
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ln Vivo |
Atuveciclib (BAY-1143572), when taken orally once daily, shows single agent efficacy at tolerated doses in 4 out of 5 AML xenograft tumor models in mice and in 2 out of 2 AML xenograft tumor models in rats. In a number of models, partial or even total remissions could be accomplished[1]. Blood cells from rats treated with Atuveciclib (BAY-1143572) also show inhibition of MYC mRNA, suggesting the potential clinical use of MYC in blood cells as a pharmacodynamic marker in clinical development. When combined with multiple chemotherapeutics, the in vivo efficacy of Atuveciclib (BAY-1143572) is markedly increased in various solid tumor models[2].
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Enzyme Assay |
Atuveciclib, formerly known as BAY-1143572, is a brand-new, potent, oral PTEFb/CDK9 inhibitor that exhibits high selectivity. With an IC50 of 13 nM, it inhibits CDK9/CycT1 and is more than 100-fold more selective for CDK9 than CDK2. Moreover, it inhibits GSK3 kinase, with IC50 values for GSK3α and GSK3β of 45 nM and 87 nM, respectively.
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Cell Assay |
BAY 1143572 exhibits antiproliferative activity against MOLM-13 cells (IC50 = 310 nM) and HeLa cells (IC50 = 920 nM). Additionally, compared to lead compound BAY-958 (PappA→B: 22 nm/s, ER: 15), it exhibits better Caco-2 permeability and a lower efflux ratio (PappA→B: 35 nm/s, ER: 6).
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Animal Protocol |
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References |
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Molecular Formula |
C18H18FN5O2S
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Molecular Weight |
387.43
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Exact Mass |
387.12
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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 # |
1414943-88-6
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Related CAS # |
Atuveciclib;2923012-24-0;Atuveciclib S-Enantiomer;2250279-81-1
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Appearance |
Solid powder
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SMILES |
COC1=C(C=CC(=C1)F)C2=NC(=NC=N2)NC3=CC=CC(=C3)CS(=N)(=O)C
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InChi Key |
ACWKGTGIJRCOOM-UHFFFAOYSA-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)
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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 |
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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 |
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
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.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT01938638 | Completed | Drug: BAY1143572 | Neoplasms | Bayer | September 26, 2013 | Phase 1 |
NCT02345382 | Terminated | Drug: Atuveciclib, BAY1143572 | Leukemia | Bayer | February 19, 2015 | Phase 1 |
Antitumor efficacy in two AML models in mice and rats. A, B: Antitumor efficacy of BAY 1143572 in an MOLM‐13 human AML model in mice.ChemMedChem. 2017 Nov 8; 12(21): 1776–1793. th> |
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Antitumor efficacy of BAY‐958 hydrochloride in an MOLM‐13 human AML model in mice.ChemMedChem. 2017 Nov 8; 12(21): 1776–1793. td> |
Docking mode of BAY‐958 in complex with CDK9. X‐ray structure ofN‐acetyl derivative33.ChemMedChem. 2017 Nov 8; 12(21): 1776–1793. td> |