CCT128930 hydrochloride is a potent and selective AKT inhibitor, with an IC50 of 6 nM. It exhibits 28-fold selectivity against the closely related PKA kinase, with an IC50 of 168 nM, and 20-fold selectivity over p70S6K, with an IC50 of 120 nM. This selectivity is achieved through targeting Met282 of AKT (Met173 of PKA-AKT chimera). CCT128930 hydrochloride induces cell cycle arrest, DNA damage, and autophagy, demonstrating significant antitumor activity[1][2].
体内研究
CCT128930 hydrochloride (25 or 40 mg/kg; i.p. daily or twice daily for 5 days) exhibits antitumor effects in U87MG glioblastoma and BT474 human breast cancer xenograft models[1].
Summary of the pharmacokinetic parameters for CCT128930 at a dose of 25 mg/kg in CrTacNCr-Fox1nu mice[1].
体外研究
CCT128930 hydrochloride exhibits GI50 values for growth inhibition at 6.3 μM in U87MG human glioblastoma cells, 0.35 μM in LNCaP human prostate cancer cells, and 1.9 μM in PC3 human prostate cancer cells. These cell lines are all PTEN-deficient human tumor cell lines[1].
CCT128930 hydrochloride, at concentrations ranging from 0.1 to 60 μM for 1 hour in U87MG human glioblastoma cells, initially induces AKT phosphorylation at serine 473 up to 20 μM, then shows a decrease in phosphorylation at higher concentrations[1].
CCT128930 hydrochloride inhibits direct AKT substrates (Ser9 GSK3β, pThr246 PRAS40, and pT24 FOXO1/p32 FOXO3a) at concentrations of ≥5 μM and the downstream target, pSer235/236 S6RP, at concentrations of ≥10 μM. This inhibition occurs while maintaining generally constant levels of the respective total proteins and GAPDH[1].
CCT128930 hydrochloride (18.9 μM; U87MG human glioblastoma cells) triggers an increase in pSer473 AKT phosphorylation after 30 minutes, sustained up to 48 hours. The total AKT protein signal gradually declines from 8 hours to 48 hours of treatment[1].
CCT128930 hydrochloride (PTEN-null U87MG human glioblastoma cells; over a 24-hour time period) leads to an increase in the percentage of cells in the G0/G1 phase from 43.6% to 64.8%[1].
CCT128930 hydrochloride (0-10 μM; 24 hours) increases, rather than inhibits, Akt phosphorylation in HepG2 and A549 cells. At concentrations of 0-20 μM over 24 hours, CCT128930 hydrochloride suppresses cell proliferation by inducing G1 phase cell cycle arrest, through the downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27, and p53. At 20 μM, CCT128930 hydrochloride initiates apoptosis with the activation of caspase-3, caspase-9, and PARP. The same concentration range (0-20 μM; 24 hours) also increases ERK and JNK phosphorylation in HepG2 cells. Additionally, CCT128930 hydrochloride activates the DNA damage response in HepG2 cells, indicated by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1, and Chk2[2].
CCT128930 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MG-63 cells
10 nM
1 hour
Inhibited Wnt5a/ROR2-mediated cell migration
Cancer Cell Int. 2017 Nov 29;17:112.
neonatal mouse cardiomyocytes (NMCs)
5 μM
4 h
To investigate the role of Akt2 in H2-mediated protection against hypoxia/reoxygenation injury in cardiomyocytes. Results showed that CCT128930 (Akt2 selective inhibitor) did not significantly affect the protective effects of H2.
Sci Rep. 2017 Nov 1;7(1):14871
SKOV3 cells
3.33 μM and 10 μM
24 h
Inhibition of pS6 (S240/S244) and pS6 (S235/S236) expression, enhancing the effect of paclitaxel in reducing cancer cell viability
PLoS One. 2016 May 5;11(5):e0155052
HeyA8 cells
3.33 μM and 10 μM
24 h
Inhibition of pS6 (S240/S244) and pS6 (S235/S236) expression, enhancing the effect of paclitaxel in reducing cancer cell viability
PLoS One. 2016 May 5;11(5):e0155052
HEK293T cells
10 μM
To study the effect of CCT128930 on TRPM3 and TRPM8 channels
Cell Rep. 2024 Apr 23;43(4):114108
HEK293T cells
10 μM
To study the effect of CCT128930 on TRPM6 channels
Cell Rep. 2024 Apr 23;43(4):114108
HEK293T cells
10 μM
To study the inhibitory effect of CCT128930 on TRPM7 channels
Cell Rep. 2024 Apr 23;43(4):114108
PC3 and LNCaP human prostate cancer cells
3 or 10 μM
1 h
To evaluate the effect of CCT128930 on AKT and its downstream proteins in different cell lines. Results showed that CCT128930 significantly inhibited the phosphorylation of GSK3β and S6RP in PTEN-null PC3 and LNCaP cells.
Mol Cancer Ther. 2011 Feb;10(2):360-71
U87MG human glioblastoma cells
18.9 μM
30 min to 48 h
To evaluate the time-dependent effect of CCT128930 on AKT activity. Results showed that CCT128930 induced phosphorylation of AKT Ser473 within 30 min, which was sustained for 48 h. Meanwhile, CCT128930 significantly inhibited the phosphorylation of GSK3β, PRAS40, FOXO3a, and S6RP.
Mol Cancer Ther. 2011 Feb;10(2):360-71
U87MG human glioblastoma cells
5-20 μM
1 h
To evaluate the effect of CCT128930 on the phosphorylation of AKT and its downstream proteins. Results showed that CCT128930 significantly inhibited the phosphorylation of direct and indirect targets of AKT (e.g., GSK3β, S6RP, FOXO1, and PRAS40) at concentrations of 5-20 μM.
Mol Cancer Ther. 2011 Feb;10(2):360-71
CCT128930 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Myocardial ischemia/reperfusion injury model
Intravenous injection
50 mg/kg
Once, 1 hour before reperfusion
To investigate the role of Akt2 in HCH-induced cardioprotection against myocardial I/R injury. Results showed that CCT128930 treatment did not significantly affect the cardioprotective effects of HCH.
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