CCT128930

AKT inhibitor CAS# 885499-61-6

CCT128930

2D Structure

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CCT128930

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Chemical Properties of CCT128930

Cas No. 885499-61-6 SDF Download SDF
PubChem ID 17751819 Appearance Powder
Formula C18H20ClN5 M.Wt 341.84
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 36.67 mg/mL (107.27 mM; Need ultrasonic)
Chemical Name 4-[(4-chlorophenyl)methyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amine
SMILES C1CN(CCC1(CC2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4
Standard InChIKey RZIDZIGAXXNODG-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of CCT128930

DescriptionCCT128930 is a potent, ATP-competitive and selective inhibitor of Akt2 with IC50 of 6 nM.
TargetsAkt2p70 S6KPKA   
IC506 nM120 nM168 nM    

Protocol

Kinase Assay [1]
Profiling against 50 different human kinases is carried out using 10 μM CCT128930 at an ATP concentration equivalent to the Km for each enzyme. All other enzyme assays are performed[1].

Cell Assay [1]
All cell lines are grown in their recommended culture medium, supplemented with 10% fetal bovine serum at 37°C in 5% CO2 and passaged for less than six months prior to replacement from early passage frozen stocks. CCT128930 and LY294002 are made up as 10mM stocks in DMSO. Cells are regularly screened for Mycoplasma using a PCR-based 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, and GI50 values are derived[1].

Animal Administration [1]
Mice[1] PTEN-null U87MG human glioblastoma cells (2×106) are injected subcutaneously (s.c.) in the right flank of 6-8 weeks old female CrTacNCr-Fox1nu mice. For HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, cells (5×106) are administered s.c. in medium supplemented with matrigel (1:1) into the mammary fat pads of female mice implanted s.c. with estradiol pellets (0.025 mg, 90 day release) 3 days previously. Animals are randomized and treatment is started with vehicle or CCT128930 when established tumors are ~100 mm3 in mean volume. Control mice receive vehicle only (10% DMSO, 5% Tween 20, 85% saline) and treated mice received 50 mg/kg CCT128930 intraperitoneally (i.p.) daily for 5 days (U87MG human glioblastoma xenografts) or 40 mg/kg CCT128930 i.p. twice daily for 5 days (BT474 human breast cancer xenografts). Tumor size and body weight are monitored three times a week. Tumor size is evaluated by measurement of 2 orthogonal diameters with calipers and volume is calculated. At the end of the study, tumors are excised and weighed.

References:
[1]. Yap TA et al. Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol Cancer Ther. 2011 Feb;10(2):360-71.

CCT128930 Dilution Calculator

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CCT128930 Molarity Calculator

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Preparing Stock Solutions of CCT128930

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.9253 mL 14.6267 mL 29.2535 mL 58.5069 mL 73.1336 mL
5 mM 0.5851 mL 2.9253 mL 5.8507 mL 11.7014 mL 14.6267 mL
10 mM 0.2925 mL 1.4627 mL 2.9253 mL 5.8507 mL 7.3134 mL
50 mM 0.0585 mL 0.2925 mL 0.5851 mL 1.1701 mL 1.4627 mL
100 mM 0.0293 mL 0.1463 mL 0.2925 mL 0.5851 mL 0.7313 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on CCT128930

CCT128930 is a potent, selective, novel and ATP-competitive inhibitor for AKT2 (IC50= 6 nM). It also has 28-fold and 20-fold selectivity over PKA kinase (IC50= 168 nM) and p70S6K (IC50= 120 nM), respectively.

Akt (protein kinase B) is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.

In multi tumor cell line, CCT128930 showed antiproliferative effect and blocked the phosphorylation of various Akt substrates. In PTEN-null human glioblastoma cells (U87MG), CCT128930 treatment led to a G1 arrest associated with Akt pathway suppression. [1]

In U87MG tumor xenografts, CCT128930 inhibited the phosphorylation of Akt downstream biomarkers. In U87MG, HER-2 positive and IK3CA-mutant BT474 human breast cancer xenografts, antitumor activity were recorded as tumor volume decreased. CCT128930-treated mouse whisker folliciles in vivo and human hair follicles treated ex vivo exerted prominent reduction in pThr246 PRAS40. [1]

Reference:
1. Yap TA, Walton MI, Hunter LJ et al.  Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol Cancer Ther. 2011 Feb;10(2):360-71.

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References on CCT128930

CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition.[Pubmed:24793486]

Biochimie. 2014 Aug;103:118-25.

PI3K/Akt/mTOR pathway plays an important role in tumor progression and anti-cancer drug resistance. The aim of the present study is to determine the antitumor effect of CCT128930, a novel small molecule inhibitor of Akt, in the HepG2 hepatoma cancer cells. Our results showed that at low concentrations, CCT128930 increased, but not inhibited, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 inhibited cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. A higher dose (20 muM) of CCT128930 triggered cell apoptosis with activation of caspase-3, caspase-9, and PARP. Treatment with CCT128930 increased phosphorylation of ERK and JNK in HepG2 cells. CCT128930 activated DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2. Upon exposure to CCT128930 at a higher concentration, HepG2 cells exhibited autophagy was accompanied by an increase the levels of LC3-II and Beclin-1. Blocking autophagy using chloroquine magnified CCT128930-induced apoptotic cell death and the phosphorylation of H2AX. The results in this study have advanced our current understandings of the anti-cancer mechanisms of CCT128930 in cancer cells.

Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930.[Pubmed:21191045]

Mol Cancer Ther. 2011 Feb;10(2):360-71.

AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G(1) arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials.

Description

CCT128930 is a potent and selective inhibitor of Akt2 (IC50 6 nM) with 28-fold selectivity over the closely related PKA kinase (IC50 168 nM), as well as 20-fold selectivity over p70S6K (IC50 120 nM).

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