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Purity: =99.88%
CCT128930 is a brand-new, potent, ATP-competitive, and selective pyrrolopyrimidine-based inhibitor of Akt2 with potential anticancer activity (IC50 = 6 nM in a cell-free assay). It revealed Akt2 to be 28 times more selective than the related PKA kinases. Drug design methods based on fragment and structure-based approaches led to the discovery of CCT128930. In vitro experiments using several tumor cell lines revealed that CCT128930 had pronounced antiproliferative effects and prevented the phosphorylation of a variety of AKT substrates, which is consistent with AKT inhibition. To sum up, CCT128930 is a brand-new, powerful, and selective AKT inhibitor that inhibits AKT activity both in vitro and in vivo and significantly increases antitumor responses.
Targets |
Akt2 (IC50 = 6 nM); p70S6K (IC50 = 120 nM); PKA (IC50 = 168 nM); Autophagy; Apoptosis
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ln Vitro |
CCT128930 has GI50 values of 6.3 M for human glioblastoma cells (U87MG), 0.35 M for human prostate cancer cells (LNCaP), and 1.9 M for human prostate cancer cells (PC3), all of which are PTEN-deficient human tumor cell lines[1].
The human glioblastoma cell line U87MG exhibits an initial induction of AKT phosphorylation at serine 473 up to 20 M, followed by a decrease in phosphorylation at higher concentrations[1] when exposed to the chemical compound CCT128930 (0.1-60 M; 1 hour).
With relatively constant levels of the corresponding total proteins and GAPDH, CCT128930 inhibits the downstream target, pSer235/236 S6RP, at 10 M, and the direct substrates of AKT (Ser9 GSK3, pThr246 PRAS40, and pT24 FOXO1/p32 FOXO3a) at 5 M[1].
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ln Vivo |
CCT128930 at 25 mg/kg i.p. shows a marked antitumor effect in established PTEN-null U87MG human glioblastoma xenografts with a treated:control (T/C) ratio of 48% on day 12. CCT128930 at 40 mg/kg also exerts a potent antitumor effect in HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, with complete growth arrest and a T/C ratio of 29% on day 22. When given intravenously, CCT128930 reaches a plasma peak concentration of 6.4 M before being rapidly cleared with a high volume of distribution, a short half-life, and an area under the curve (AUC0-) of 4.6 M h. I.p. administration of CCT128930 results in a peak plasma drug concentration of 1.3 M and an associated AUC0- of 1.3 Mh. When CCT128930 is taken orally, the peak plasma concentration is only 0.43 M, and the AUC0- is a low 0.4 Mh.[1]
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Enzyme Assay |
Profiling against 50 different human kinases is carried out using 10 μM CCT128930 at an ATP concentration equivalent to the Km for each enzyme.
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Cell Assay |
Cells are seeded in 96-well plates and allowed to attach for 36 hours to ensure exponential growth prior to treatment. In vitro antiproliferative activity is determined using a 96-hour SRB assay. TCA-fixed cells are stained for 30 minutes with 0.4% (wt/vol) SRB dissolved in 1% acetic acid. At the end of the staining period, SRB is removed and cultures are quickly rinsed four times with 1% acetic acid to remove unbound dye. The acetic acid is poured directly into the culture wells from a beaker. This procedure permits rinsing to be performed quickly so that desorption of protein-bound dye does not occur. Residual wash solution is removed by sharply flicking plates over a sink, which ensures the complete removal of rinsing solution. Because of the strong capillary action in 96-well plates, draining by gravity alone often fails to remove the rinse solution when plates are simply inverted. After being rinsed, the cultures are air dried until no standing moisture is visible. Bound dye is solubilized with 10 mM unbuffered Tris base (pH 10.5) for 5 minutes on a gyratory shaker. OD is read in either a UVmax microtiter plate reader or a Beckman DU-70 spectrophotometer. For maximum sensitivity, OD is measured at 564 nm. Because readings are linear with dye concentrations only below 1.8 OD units, however, suboptimal wavelengths are generally used, so that all samples in an experiment remains within the linear OD range. With most cell lines, wavelengths of approximately 490-530 nm works well for this purpose.
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Animal Protocol |
6-8 weeks old female CrTacNCr-Fox1nu mice[1]
25 mg/kg (U87MG human glioblastoma xenografts) or 40 mg/kg (BT474 human breast cancer xenografts) i.p. daily for 5 days (U87MG human glioblastoma xenografts); i.p. twice daily for 5 days (BT474 human breast cancer xenografts) |
References |
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Molecular Formula |
C18H20CLN5
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Molecular Weight |
341.84
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Exact Mass |
341.14
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Elemental Analysis |
C, 63.24; H, 5.90; Cl, 10.37; N, 20.49
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CAS # |
885499-61-6
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Related CAS # |
CCT128930 hydrochloride;2453324-32-6
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Appearance |
Solid powder
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SMILES |
NC1(CC2=CC=C(Cl)C=C2)CCN(C3=C4C(NC=C4)=NC=N3)CC1
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InChi Key |
RZIDZIGAXXNODG-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C18H20ClN5/c19-14-3-1-13(2-4-14)11-18(20)6-9-24(10-7-18)17-15-5-8-21-16(15)22-12-23-17/h1-5,8,12H,6-7,9-11,20H2,(H,21,22,23)
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Chemical Name |
4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amine
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Synonyms |
CCT128930; CCT-128930; CCT 128930
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.08 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 (6.08 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 (6.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO+30% polyethylene glycol+1% Tween 80: 11mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.9253 mL | 14.6267 mL | 29.2535 mL | |
5 mM | 0.5851 mL | 2.9253 mL | 5.8507 mL | |
10 mM | 0.2925 mL | 1.4627 mL | 2.9253 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.
Effect of CCT128930 exposure on expression of AKT biomarkers and cell cycle proteins in a panel of human tumor cell lines. Mol Cancer Ther. 2011, 10(2), 360-371. td> |
Pharmacokinetic behavior and pharmacodynamic effects of CCT128930 in vivo. td> |
Antitumor activity of CCT128930 in human tumor xenografts. td> |