CC-223

CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. CC-223 inhibits both mTORC1 and mTORC2.

Product information

CAS Number: 1228013-30-6

Molecular Weight: 397.47

Formula: C21H27N5O3

Chemical Name: 7-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(1r,4r)-4-methoxycyclohexyl]-1H,2H,3H,4H-pyrazino[2,3-b][1,4]diazin-2-one

Smiles: CC(C)(O)C1C=CC(=CN=1)C1=CN=C2NCC(=O)N([C@@H]3CC[C@H](CC3)OC)C2=N1

InChiKey: UFKLYTOEMRFKAD-SHTZXODSSA-N

InChi: 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)/t14-,15-

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO : ≥ 27 mg/mL (67.93 mM).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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) .

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.

Products are for research use only. Not for human use.