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].
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