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Purity: ≥98%
Onatasertib (CC-223; CC223) is a potent, selective, and orally bioavailable mTOR (mammalian target of rapamycin) kinase inhibitor with anticancer activity. mTOR is a serine/threonine kinase that is upregulated in various tumors, and plays an important role downstream in the PI3K/AKT/mTOR signaling pathway, which is frequently dysregulated in human cancers. CC-223 demonstrated inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. CC-223 is selective for mTOR kinase with >200-fold selectivity over the related PI3K-α (IC50=4.0 μM). Of the PI3K related kinases tested, CC-223 shows no significant inhibition of ATR or SMG1 and inhibits DNA-PK with an IC50 value of 0.84 μM.
| Targets |
mTOR (IC50 = 16 nM); DNA-PK (IC50 = 0.84 μM); PI3K-α (IC50 = 4 μM); mTORC1; mTORC2
Onatasertib (CC-223) targets mTOR kinase (including mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)); [1] |
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| ln Vitro |
In a panel of cell lines, CC-223 inhibits both mTORC1 (S6RP and 4EBP1) and mTORC2 [AKT(S473)] markers with IC50 ranges of 27 to 184 nM for pS6RP, 120 to 1,050 nM for p4EBP1 and 11 to 150 nM for pAKT(S473), respectively. Additionally, CC-223 causes apoptosis and slows cell growth in a variety of cancer cell lines. [1]
1. Onatasertib (CC-223) is a potent, selective inhibitor of mTOR kinase, which could inhibit the activation of mTORC1 (characterized by the reduction of phosphorylated S6 ribosomal protein (pS6RP) and phosphorylated 4E-binding protein 1 (p4EBP1)) and mTORC2 (characterized by the reduction of phosphorylated AKT at serine 473 (pAKT(S473))) in cellular systems [1] 2. Onatasertib (CC-223) exhibited growth inhibitory activity in a variety of hematologic and solid tumor cell lines; compared with rapamycin (an allosteric inhibitor targeting only mTORC1), Onatasertib (CC-223) achieved more complete inhibition of mTOR pathway biomarkers and showed improved antiproliferative activity in cells [1] 3. In a panel of hematologic cancer cell lines, Onatasertib (CC-223) induced growth inhibition and apoptosis; correlative analysis indicated that the expression level of IRF4 was associated with resistance to Onatasertib (CC-223), while the activation status of the mTOR pathway was correlated with sensitivity to the drug [1] |
| ln Vivo |
In PC-3 tumor-bearing mice, CC-223 (25 mg/kg, p.o.) inhibits both mTORC1 and mTORC2. CC-223 (25 mg/kg, p.o.) also results in tumor growth inhibition by 47% to 95% in xenograft models of prostate, glioma, breast, lung, and colon. [1]
1. After a single oral administration of Onatasertib (CC-223) to tumor-bearing mice, significant inhibition of tumor biomarkers related to the mTOR pathway was observed in tumor tissues [1] 2. Onatasertib (CC-223) showed dose-dependent tumor growth inhibition in multiple solid tumor xenograft models; detection of mTOR pathway markers in tumor tissues from treated mice revealed that pS6RP and pAKT were significantly inhibited, suggesting that the antitumor activity of Onatasertib (CC-223) was mediated by the simultaneous inhibition of mTORC1 and mTORC2 [1] |
| Enzyme Assay |
Counter screen against 246 protein kinases is outsourced and completed at a fixed CC-223 concentration (10 μM). Ephrin type-B receptor 3 kinase (EPHB3), colony stimulating factor 1 receptor tyrosine kinase (CSF1R or cFMS), and FMS-related tyrosine kinase 4 (FLT4) follow-up IC50 value determinations are contracted out to Invitrogen.
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| Cell Assay |
Compound is spotted into a 384-well plate that is not already filled using an acoustic dispenser (EDC ATS-100). Directly onto the compound-spotted plates, cells are added after being diluted to the desired density. For 72 hours, cells are permitted to grow. Utilizing Cell Titer-Glo, viability is evaluated. All data are normalized and shown as a percentage of the cells that received DMSO treatment. The GI50 and/or IC50 values of the results are then presented.
1. For evaluating the antiproliferative activity of Onatasertib (CC-223), a variety of hematologic and solid tumor cell lines were cultured and treated with different concentrations of the drug; the cell proliferation status was detected, and the inhibitory effect was compared with that of rapamycin to analyze the completeness of mTOR pathway inhibition and the strength of antiproliferative activity [1] 2. Western blot technology was used to detect the protein levels of mTOR pathway-related biomarkers (pS6RP, p4EBP1, pAKT(S473)) in cells treated with Onatasertib (CC-223), so as to verify the inhibitory effect of the drug on both mTORC1 and mTORC2 [1] 3. A panel of hematologic cancer cell lines were treated with Onatasertib (CC-223), and then the cell growth status and apoptosis rate were detected; correlative analysis was conducted to explore the relationship between IRF4 expression level, mTOR pathway activation and the efficacy of Onatasertib (CC-223) [1] |
| Animal Protocol |
Mice: Female CB17 SCID mice aged 6 to 8 weeks are s.c. inoculated with 2 106 PC-3 cells. Mice are randomized and treated once daily, twice daily, or every two days with vehicle or various doses of CC-223 at a dose volume of 5 mL/kg starting when tumors measure about 125 mm3. The morning and evening doses of the twice-daily medications are spaced apart by 10 hours. The starting volumes are the tumor volumes, which are established prior to the start of treatment. Throughout the course of the study, tumors are measured twice per week. A digital caliper is used to measure each tumor's long and short axes in millimeters. Volumes of the tumor are calculated. The cubic millimeters (mm3) used to express tumor volumes.
1. Onatasertib (CC-223) was administered to tumor-bearing mice via oral route at a single dose; at the corresponding time point after administration, tumor tissues were collected, and the expression levels of mTOR pathway biomarkers (pS6RP, p4EBP1, pAKT(S473)) were detected to evaluate the in vivo inhibitory effect of the drug on the mTOR pathway [1] 2. Mice bearing multiple types of solid tumor xenografts were treated with Onatasertib (CC-223) via oral route at different doses (specific dose gradient was not specified); the tumor volume was regularly measured to evaluate the dose-dependent tumor growth inhibition effect of the drug; after the experiment, tumor tissues were collected to detect the levels of pS6RP and pAKT, so as to clarify the mechanism of antitumor activity [1] |
| References | |
| Additional Infomation |
Onatasertib (CC-223) has been used in clinical trials and basic science studies for the treatment of various cancers, including multiple myeloma, glioblastoma multiforme, hepatocellular carcinoma, non-small cell lung cancer, and diffuse large B-cell lymphoma. Onatasertib is an orally administered mammalian target of rapamycin (mTOR) inhibitor with potential antitumor activity. Onatasertib inhibits mTOR activity, thereby inducing tumor cell apoptosis and reducing tumor cell proliferation. mTOR is a serine/threonine kinase upregulated in various tumors and plays an important role downstream of the PI3K/AKT/mTOR signaling pathway, which is frequently abnormal in human cancers.
1. mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation and survival; mTORC1 and mTORC2 are key mediators of the PI3K-AKT signaling pathway, which is frequently mutated in various cancers, leading to overactivation of mTOR signaling[1] 2. Rapamycin analogues are allosteric inhibitors that target only mTORC1 and have shown certain clinical activity in cancer treatment; mTOR kinase inhibitors, represented by Onatasertib (CC-223), can block both mTORC1 and mTORC2 signaling and are considered to have broader therapeutic potential[1] 3. At the time of publication, Onatasertib (CC-223) was undergoing a Phase I clinical trial for cancer treatment[1] |
| Molecular Formula |
C21H27N5O3
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| Molecular Weight |
397.47
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| Exact Mass |
397.211
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| Elemental Analysis |
C, 63.46; H, 6.85; N, 17.62; O, 12.08
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| CAS # |
1228013-30-6
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| Related CAS # |
1228013-30-6;
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| PubChem CID |
58298316
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| Appearance |
Red to pink solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
656.3±55.0 °C at 760 mmHg
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| Flash Point |
350.7±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.630
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| LogP |
-0.03
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
581
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])[H])C1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C(C([H])([H])N([H])C2C1=NC(C1=C([H])N=C(C([H])=C1[H])C(C([H])([H])[H])(C([H])([H])[H])O[H])=C([H])N=2)=O
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| InChi Key |
UFKLYTOEMRFKAD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H27N5O3/c1-21(2,28)17-9-4-13(10-22-17)16-11-23-19-20(25-16)26(18(27)12-24-19)14-5-7-15(29-3)8-6-14/h4,9-11,14-15,28H,5-8,12H2,1-3H3,(H,23,24)
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| Chemical Name |
3-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-5-(4-methoxycyclohexyl)-7,8-dihydropyrazino[2,3-b]pyrazin-6-one
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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: ≥ 1.25 mg/mL (3.14 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 12.5 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: ≥ 1.25 mg/mL (3.14 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 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5159 mL | 12.5796 mL | 25.1591 mL | |
| 5 mM | 0.5032 mL | 2.5159 mL | 5.0318 mL | |
| 10 mM | 0.2516 mL | 1.2580 mL | 2.5159 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 | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02031419 | Active Recruiting |
Drug: CC-122 Drug: CC-223 |
Lymphoma, Large B-Cell, Diffuse |
Celgene | December 18, 2013 | Phase 1 |
| NCT01896323 | Completed | Drug: CC-223 Drug: Ketoconazole |
Healthy Volunteers | Celgene | July 1, 2013 | Phase 1 |
| NCT01611467 | Completed | Drug: CC-223 | Safety and Pharmacokinetics in Healthy Volunteer Subjects |
Celgene | June 1, 2012 | Phase 1 |
| NCT01177397 | Completed | Drug: CC-223 | Multiple Myeloma Glioblastoma Multiforme |
Celgene | July 20, 2010 | Phase 1 Phase 2 |
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