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| Cas No.: | 1228013-30-6 |
| Chemical Name: | Cc-223 |
| Synonyms: | CC-223;Onatasertib;I8RA3543SY;Onatasertib (USAN);Onatasertib [USAN];7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-5-(4-methoxycyclohexyl)-7,8-dihydropyrazino[2,3-b]pyrazin-6-one;CC223;7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one;7-(6-(2-Hydroxypropan-2-yl)pyridin-3-y |
| 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 |
| Formula: | C21H27N5O3 |
| M.Wt: | 397.4708 |
| Purity: | >98% |
| Sotrage: | 2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO |
| 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. |
| 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]. |
| 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]. |
| 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 Administration: | 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: | [1]. Mortensen DS, et al. CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization. Mol Cancer Ther. 2015 Jun;14(6):1295-305. |
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| LOT NO. | DOWNLOAD |
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| 2018-0101 |
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| 2018-0101 |
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