化合物信息

Description

Cancer

Description

CCT128930 is a potent, ATP-competitive and selective inhibitor of Akt2 with IC50 of 6 nM.

Targets

IC₅₀

In Vitro

CCT128930 exhibits marked antiproliferative activity against PTEN-deficient human tumor cell lines including U87MG human glioblastoma cells, LNCaP human prostate cancer cells and PC3 human prostate cancer cells with GI50 of 6.3 μM, 0.35 μM and 1.9 μM, respectively. Furthermore, CCT128930 causes a G1 arrest in PTEN-null U87MG human glioblastoma cells and Akt pathway blockade. ^[1]

In 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. In HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, CCT128930 at 40 mg/kg also produces a profound antitumor effect with complete growth arrest and a T/C ratio of 29% on day 22. CCT128930 administrated via i.v. reaches a peak concentration of 6.4 μM in plasma and was eliminated with a relatively short half-life, high volume of distribution, and rapid clearance, giving an area under the curve AUC_0-∞ of 4.6 μM h. CCT128930 administrated via i.p. leads to the peak plasma drug concentration of 1.3 μM and the corresponding AUC_0-∞ of 1.3 μM·h. Oral CCT128930 administration leads to the peak plasma concentration of only 0.43 μM and a correspondingly low AUC_0-∞ of 0.4 μM·h. ^[1]

Clinical Trials

Features

Kinase assays

Profiling against 50 different human kinases was carried out using 10 μM CCT128930 at an ATP concentration equivalent to the K_m for each enzyme.

Cell Lines

U87MG, LNCaP and PC3 cells

Concentrations

0-18.9 μM

Incubation Time

48 hours

Methods

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.

Animal Models

PTEN-null U87MG human glioblastoma cells are injected subcutaneously (s.c.) in the right flank of female CrTacNCr-Fox1nu mice. For HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, cells 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.

Formulation

CCT128930 is dissolved in 10% DMSO, 5% Tween 20, and 85% saline.

Doses

≤50 mg/kg

Administration

Administered via i.p.