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| Targets |
Cenisertib targets aurora kinases (AKs), including Aurora A, Aurora B, and Aurora C, which are overexpressed in certain types of cancer. By selectively binding to and inhibiting these kinases, Cenisertib inhibits cell division and proliferation and induces apoptosis in tumor cells that overexpress AKs.
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| ln Vitro |
Mast cell (MC) proliferation in primary tumors is dose-dependently inhibited by ceneretib (AS-703569) (1-1000 nM; 48 hours) [1]. At low nanomolar concentrations, ceneritibibe (5-100 nM) significantly arrests the G2/M cell cycle in all MC lines over the course of 24 hours [1]. In HMC-1.1, HMC-1.2, C2, and NI-1 cells, ceneretib (1-1000 nM) causes apoptosis in a dose-dependent manner over the course of 24 hours [1]. In HMC-1 subclones, C2 and NI-1 cells, ceneretib (5-500 nM) causes caspase 3 cleavage for a duration of 24 hours [1].
In vitro, Cenisertib selectively binds to and inhibits multiple Aurora kinases, resulting in the inhibition of cell division and proliferation, and the induction of apoptosis in tumor cells that overexpress AKs. It demonstrates potent antiproliferative activity against various cancer cell lines. Detailed in vitro activity data including IC50 values are available from published studies. |
| ln Vivo |
Tumor growth was markedly suppressed by ceneritib (AS-703569) (oral; 7 or 10 mg/kg/day; for 3 days followed by 4 days of rest; for 4 weeks).
In vivo, Cenisertib has been investigated for the treatment of solid tumors, leukemia (myeloid), myelodysplastic syndrome, and other cancers. It is orally bioavailable and has demonstrated antitumor activity in preclinical models. The compound has been studied in clinical trials for its efficacy and safety in cancer patients. |
| Enzyme Assay |
In vitro kinase assays for Aurora kinase inhibition typically use recombinant Aurora A, B, or C enzymes and a suitable peptide substrate. The enzyme is incubated with ATP and the substrate in the presence of varying concentrations of Cenisertib. Kinase activity is measured by detecting phosphorylation of the substrate using radiometric or luminescence-based methods. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: HMC-1.1, HMC-1.2, ROSAKIT WT, ROSAKIT D816V and MCPV-1.1 Mast cell Tested Concentrations: 1, 5, 10, 50, 100, 500, 1000 nM Incubation Duration: 48 hrs (hours) Experimental Results: Dose-dependent inhibition of primary tumor MC proliferation. Cell cycle analysis[1] Cell Types: HMC-1.1, HMC-1.2, C2 and NI-1 Cell Tested Concentrations: 5, 10, 50, 100 nM Incubation Duration: 24 hrs (hours) Experimental Results: Induction of massive G2/M cell cycle at 7 The nanomolar concentrations of stasis were low in all MC lines. Apoptosis analysis[1] Cell Types: HMC-1.1, HMC-1.2, C2 and NI-1 Cell Tested Concentrations: 1, 5, 10, 50, 100, 500, 1000 nM Incubation Duration: 24 hrs (hours) Experimental Results: In HMC- Induced apoptosis in 1.1, HMC-1.2, C2 and NI-1 cells in a dose-dependent manner. Western Blot Analysis[1] Cell Types: HMC-1.1, HMC-1.2, C2 and NI-1 Cell Tested Concentrations: 50, 100, 500 nM Incubation Duration: 24 hrs (hours) Experimental Results: Induction of caspase 3 cleaved clones in HMC-1 subcells and in C2 and NI-1 cells. In vitro cellular assays for Aurora kinase inhibitors typically use cancer cell lines with overexpression of Aurora kinases. Cells are treated with Cenisertib at various concentrations, and cell proliferation is measured by MTT or CCK-8 assays. Cell cycle analysis is performed by propidium iodide staining and flow cytometry. Apoptosis is assessed by Annexin V/PI staining. Aurora kinase activity is measured by Western blotting for phosphorylated histone H3 (Aurora B substrate). |
| Animal Protocol |
Animal/Disease Models: NCI-MDR tumor-bearing female CB17 severe combined immunodeficiency (SCID) mice [2]
Doses: 7 and 10 mg/kg Route of Administration: Oral; daily; 3 days followed by 4 days rest; continuous 4-week Experimental Results: Dramatically inhibited tumor growth. In vivo animal studies for Aurora kinase inhibitors typically use xenograft tumor models in immunocompromised mice. Animals are implanted with cancer cells and treated with Cenisertib orally at various doses. Tumor growth is monitored by caliper measurement. Histone H3 phosphorylation and other biomarkers are assessed in tumor tissue by immunohistochemistry or Western blotting. |
| ADME/Pharmacokinetics |
Cenisertib is orally bioavailable with good absorption following oral administration. As a small-molecule kinase inhibitor, it distributes to various tissues. The compound is metabolized in the liver, and its metabolites are excreted via the kidneys and bile. Detailed PK parameters such as half-life, Cmax, and AUC are available from preclinical and clinical studies.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of Cenisertib would typically include acute and repeated-dose toxicity in rodents and dogs, as well as genotoxicity and safety pharmacology assessments. As a kinase inhibitor, potential off-target effects and myelosuppression should be monitored. The compound has been evaluated in clinical trials for safety and tolerability.
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| References | |
| Additional Infomation |
Cenisertib is an aurora kinase inhibitor. Cenisertib is a water-soluble synthetic small molecule with potential antitumor activity. Cenisertib selectively binds to and inhibits aurora kinases (AKs), a class of serine/threonine kinases that are important regulators of cell division and proliferation and are overexpressed in certain types of cancer. Inhibition of AKs inhibits cell division and proliferation and induces apoptosis in tumor cells that overexpress AKs. Drug Indications It has been investigated for the treatment of solid tumors, myeloid leukemia, myelodysplastic syndromes, and unspecified types of cancer/tumors. Mechanism of Action R763 is a potent and specific aurora kinase inhibitor that has been shown to block the proliferation of various tumor cell lines, including cervical cancer, colon cancer, lung cancer, pancreatic cancer, and prostate cancer, and induce apoptosis (cell death). Overexpression of AKs can lead to the rapid production of an abnormal number of chromosomes in cells. Elevated levels of aurora kinase are commonly associated with a variety of human cancers; inhibiting this enzyme can disrupt cell division and promote apoptosis. [Rigel Pharmaceuticals Press Release] One potential target of R763 is Aurora kinase A (serine/threonine protein kinase 6).
Cenisertib (AS-703569, R763) is an orally bioavailable Aurora kinase inhibitor with potential antineoplastic activity. It selectively binds to and inhibits Aurora kinases, which are important regulators of cell division. The compound has been investigated for the treatment of solid tumors, leukemia, and myelodysplastic syndrome. It is available for research use. |
| Molecular Formula |
C24H30FN7O
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|---|---|
| Molecular Weight |
451.54
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| Exact Mass |
451.249
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| CAS # |
871357-89-0
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| PubChem CID |
11569967
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
708.3±70.0 °C at 760 mmHg
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| Flash Point |
382.2±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.669
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| LogP |
0.76
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
730
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CC1=C(C=CC(=C1)NC2=NC=C(C(=N2)N[C@@H]3[C@@H]4C[C@H]([C@@H]3C(=O)N)C=C4)F)N5CCN(CC5)C
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| InChi Key |
KSOVGRCOLZZTPF-QMKUDKLTSA-N
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| InChi Code |
InChI=1S/C24H30FN7O/c1-14-11-17(5-6-19(14)32-9-7-31(2)8-10-32)28-24-27-13-18(25)23(30-24)29-21-16-4-3-15(12-16)20(21)22(26)33/h3-6,11,13,15-16,20-21H,7-10,12H2,1-2H3,(H2,26,33)(H2,27,28,29,30)/t15-,16+,20+,21-/m1/s1
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| Chemical Name |
(1S,2S,3R,4R)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide
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| Synonyms |
R-763; R 763; R763
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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 : ~250 mg/mL (~553.66 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.61 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 (4.61 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 (4.61 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 | 2.2146 mL | 11.0732 mL | 22.1464 mL | |
| 5 mM | 0.4429 mL | 2.2146 mL | 4.4293 mL | |
| 10 mM | 0.2215 mL | 1.1073 mL | 2.2146 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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