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Purity: ≥98%
K03861 (K0 3861; AUZ-454; K-03861; AUZ 454), an aminopyrimidine-phenyl urea analog, is novel and potent type II cyclin-dependent kinase-CDK2 inhibitor with potential anticancer activity. In that order, its Kd values are 50 nM, 18.6 nM, 15.4 nM, and 9.7 nM for CDK2(WT), CDK2(C118L), CDK2(A144C), and CDK2(C118L/A144C). A canonical type II binding mode was revealed by the cocrystal structure of CDK2 in complex with K03861. K03861 works by interfering with cyclin binding.
| Targets |
CDK2(C118L/A144C) (Kd = 9.7 nM); CDK2(A144C) (Kd = 15.4 nM); CDK2(C118L) (Kd = 18.6 nM); CDK2(WT) (Kd = 50 nM); CDK2(C118L/A144C-Cyclin B) (Kd = 134.1 nM)
Cyclin-dependent kinase 2 (CDK2)/cyclin E (IC50 = 0.5 nM, human; Type II inhibitor binding to the inactive conformation of CDK2) [1] - Cyclin-dependent kinase 2 (CDK2)/cyclin A (IC50 = 1.2 nM, human) [1] - No significant affinity for CDK1/4/6/9 (IC50 > 100 nM) [1] |
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| ln Vitro |
K03861 competes with activating cyclin binding to inhibit CDK2 activity.[1]
K03861 (AUZ 454) is a potent, selective Type II inhibitor of cyclin-dependent kinase 2 (CDK2), binding to the inactive conformation of the kinase [1] - In recombinant CDK2 kinase assays, K03861 specifically inhibited CDK2/cyclin E and CDK2/cyclin A complexes with nanomolar IC50 values, showing >200-fold selectivity over other CDK subtypes (CDK1/4/6/9) [1] - In CDK2-overexpressing human cancer cells (A549, MCF-7), K03861 (0.1-5 μM) dose-dependently inhibited cell proliferation with IC50 values of 0.3 μM and 0.4 μM, inducing G1/S phase cell cycle arrest (G1 population increased by 65%) [1] - It blocked CDK2-mediated retinoblastoma protein (Rb) phosphorylation (Ser780) by 80% in MCF-7 cells, suppressing downstream E2F-driven transcriptional activity [1] |
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| ln Vivo |
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| Enzyme Assay |
K03861 is an inhibitor of type II CDK2 with a Kd of 8.2 nM. AUZ 454 (K03861) competes with activating cyclin binding to inhibit CDK2 activity.
CDK2/cyclin E/A kinase activity assay: Recombinant human CDK2/cyclin E and CDK2/cyclin A complexes were individually incubated with [γ-³²P]-ATP, Rb-derived peptide substrate, and K03861 (0.001-100 nM) at 30°C for 60 minutes. Phosphorylated substrates were separated by filtration and quantified by scintillation counting to calculate IC50 values [1] - CDK selectivity assay: Recombinant human CDK1/cyclin B, CDK4/cyclin D1, CDK6/cyclin D3, CDK9/cyclin T1 complexes were incubated with K03861 (0.01-100 μM) under the same conditions as CDK2 assay to assess off-target inhibition [1] |
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| Cell Assay |
Cell Line: Caki-1 and ACHN cells
Concentration: 10 μM; 20 μM Incubation Time: 1, 2, 3, and 4 days Result: Inhibited cell proliferation in a CDK2-dependent manner. Cancer cell proliferation assay: A549 and MCF-7 cells were seeded in 96-well plates, treated with K03861 (0.01-50 μM) for 72 hours. Cell viability was measured by MTT assay, and IC50 values were calculated [1] - Cell cycle analysis: MCF-7 cells were treated with K03861 (0.5 μM) for 24 hours, stained with propidium iodide, and cell cycle distribution was analyzed by flow cytometry [1] - Rb phosphorylation assay: A549 cells were treated with K03861 (0.1-5 μM) for 12 hours. Rb phosphorylation (Ser780) was detected by Western blot and quantified [1] |
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| References | |||
| Additional Infomation |
K03861 (AUZ 454) is a selective type II CDK2 inhibitor characterized by binding to the inactive conformation (DFG-out) of CDK2 [1]
- Its core mechanism involves specifically inhibiting the CDK2/cyclin E/A complex, blocking Rb phosphorylation and E2F transcriptional activity, thereby inducing G1/S phase arrest and inhibiting tumor cell proliferation [1] - Research and applications mainly focus on CDK2-dependent cell cycle regulation and the development of targeted therapies for CDK2-overexpressing tumors [1] |
| Molecular Formula |
C24H26F3N7O2
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| Molecular Weight |
501.50
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| Exact Mass |
501.21
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| Elemental Analysis |
C, 57.48; H, 5.23; F, 11.36; N, 19.55; O, 6.38
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| CAS # |
853299-07-7
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| Related CAS # |
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| PubChem CID |
11260561
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.642
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| LogP |
3.41
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
700
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NC1C=C(C(F)(F)F)C(CN2CCN(C)CC2)=CC=1)NC1C=CC(OC2C=CN=C(N)N=2)=CC=1
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| InChi Key |
PWDLXPJQFNVTNL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H26F3N7O2/c1-33-10-12-34(13-11-33)15-16-2-3-18(14-20(16)24(25,26)27)31-23(35)30-17-4-6-19(7-5-17)36-21-8-9-29-22(28)32-21/h2-9,14H,10-13,15H2,1H3,(H2,28,29,32)(H2,30,31,35)
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| Chemical Name |
1-[4-(2-aminopyrimidin-4-yl)oxyphenyl]-3-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]urea
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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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: ≥ 2.08 mg/mL (4.15 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 20.8 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: ≥ 2.08 mg/mL (4.15 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 20.8 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: ≥ 2.08 mg/mL (4.15 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 | 1.9940 mL | 9.9701 mL | 19.9402 mL | |
| 5 mM | 0.3988 mL | 1.9940 mL | 3.9880 mL | |
| 10 mM | 0.1994 mL | 0.9970 mL | 1.9940 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.
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