1228013-30-6
1228013-30-6 structure
- Name: CC-223
- Chemical Name: 7-[6-(2-Hydroxy-2-propanyl)-3-pyridinyl]-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one
- CAS Number: 1228013-30-6
- Molecular Formula: C21H27N5O3
- Molecular Weight: 397.471
- Catalog: Research Areas Cancer
- Create Date: 2018-01-22 16:10:18
- Modify Date: 2024-01-21 16:59:19
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CC-223 is a potent inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. CC-223 inhibits both mTORC1 and mTORC2.
| Name | 7-[6-(2-Hydroxy-2-propanyl)-3-pyridinyl]-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one |
|---|---|
| Synonyms |
Pyrazino[2,3-b]pyrazin-2(1H)-one, 3,4-dihydro-7-[6-(1-hydroxy-1-methylethyl)-3-pyridinyl]-1-(trans-4-methoxycyclohexyl)-
7-[6-(2-Hydroxy-2-propanyl)-3-pyridinyl]-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one MFCD28976054 CC-223 |
| Description | CC-223 is a potent inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. CC-223 inhibits both mTORC1 and mTORC2. |
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| Related Catalog | |
| Target |
mTOR:16 nM (IC50) mTORC1 mTORC2 DNA-PK:0.84 μM (IC50) PI3K-α:4 μM (IC50) |
| In Vitro | CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating 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. When screened in a single-point assay against a commercially available panel of 246 kinases, only three kinases other than mTOR are inhibited >80% at 10 μM by CC-223. Upon follow-up IC50 value determination, only two are inhibited by CC-223 with IC50 values below 1 μM; FLT4 (0.651 μM) and cFMS (0.028 μM). The exquisite kinase selectivity of CC-223 is confirmed upon evaluation in cellular systems using ActivX KiNavtiv profiling. Other than mTOR kinase, no kinase target is identified when HCT 116 or A549 cells are treated for 1 hour with 1 μM CC-223 and assayed for kinase activity. CC-223 shows a concentration-dependent reduction in each marker, with IC50 values of 31±2 nM for pS6RP, 405±47 nM for p4EBP1, and 11±10 nM for pAKT(S473) in western blot analysis. Inhibition of these pathway biomarkers is investigated in additional cell types from a variety of tissue origins. CC-223 inhibits both mTORC1 (S6RP and 4EBP1) and mTORC2 [AKT(S473)] markers across the panel 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) [1]. |
| In Vivo | The antitumor activity of CC-223 in the PC-3 xenograft model is determined using a number of dosing paradigms. CC-223 significantly inhibits PC-3 tumor growth in a dose- and schedule-dependent manner. Dosing at 10 or 25 mg/kg, once daily, results in 46% (P<0.001) and 87% (P<0.001) reduction in tumor volume, respectively. Similar dose dependency is observed with twice-daily dosing at 5 or 10 mg/kg, corresponding to 65% (P<0.001) and 80% (P<0.001) tumor volume reductions. All dose levels are tolerated in the once-daily and twice-daily dosing studies, with only the 25 mg/kg/d group showing any significant body weight loss. These mice lost approximately 10% of their initial body weight after 3 weeks of dosing[1]. |
| Kinase Assay | Counter screen against 246 protein kinases is outsourced and completed at a fixed CC-223 concentration (10 μM). Follow-up IC50 value determinations for ephrin type-B receptor 3 kinase (EPHB3), colony stimulating factor 1 receptor tyrosine kinase (CSF1R or cFMS), and FMS-related tyrosine kinase 4 (FLT4) are outsourced to Invitrogen[1]. |
| Cell Assay | For other cell panel proliferation assays, CC-223 (1 nM, 100 nM and 1 μM) is spotted via an acoustic dispenser (EDC ATS-100) into an empty 384-well plate. Cells are diluted to desired densities and added directly to the compound-spotted plates. Cells are allowed to grow for 72 hours. Viability is assessed via Cell Titer-Glo. All data are normalized and represented as a percentage of the DMSO-treated cells. Results are then expressed as GI50 and/or IC50 values[1]. |
| Animal Admin | Mice[1] Female 6- to 8-weeks-old CB17 SCID mice are inoculated s.c. with 2×106 PC-3 cells. When tumors reach approximately 125 mm3, mice are randomized and treated once daily, twice daily, or every 2 days orally with vehicle or various doses of CC-223, at a dose volume of 5 mL/kg. The twice-daily doses are administered with a 10 hours separation between the morning and evening doses. Tumor volumes are determined before the initiation of treatment and are considered as the starting volumes. Tumors are measured twice a week for the duration of the study. The long and short axes of each tumor are measured using a digital caliper in millimeters. The tumor volumes are calculated. The tumor volumes are expressed in cubic millimeters (mm3). |
| References |
| Density | 1.3±0.1 g/cm3 |
|---|---|
| Boiling Point | 656.3±55.0 °C at 760 mmHg |
| Molecular Formula | C21H27N5O3 |
| Molecular Weight | 397.471 |
| Flash Point | 350.7±31.5 °C |
| Exact Mass | 397.211395 |
| LogP | -0.03 |
| Vapour Pressure | 0.0±2.1 mmHg at 25°C |
| Index of Refraction | 1.630 |
| Storage condition | -20℃ |