CCT128930

CCT128930 is a ATP-competitive and selective inhibitor of AKT (IC₅₀=6 nM for AKT2). CCT128930 has 28-fold selectivity over the closely related PKA kinase (IC₅₀=168 nM) through the targeting of Met282 of AKT (Met173 of PKA-AKT chimera), as well as 20-fold selectivity over p70S6K (IC₅₀=120 nM). Antitumor activity. IC50 & Target: IC50: 6 nM (Akt2), 120 nM (p70S6K), 168 nM (PKA kinase)^[1] In Vitro: The GI₅₀ values of CCT128930 for growth inhibition are 6.3 μM for U87MG human glioblastoma cells, 0.35 μM for LNCaP human prostate cancer cells, and 1.9 μM for PC3 human prostate cancer cells, all of which are PTEN-deficient human tumor cell lines^[1].
CCT128930 (0.1-60 μM; 1 hour; U87MG human glioblastoma cells) shows an initial induction of AKT phosphorylation at serine 473 up to 20 μM, followed by a decreased in phosphorylation at higher concentrations^[1].
CCT128930 inhibits direct substrates of AKT (Ser9 GSK3β, pThr246 PRAS40 and pT24 FOXO1/p32 FOXO3a) at ≥5 μM, and the downstream target, pSer235/236 S6RP at ≥ 10 μM, with generally constant levels of the respective total proteins and GAPDH^[1].
CCT128930 (18.9 μM; U87MG human glioblastoma cells) causes an increase in phosphorylation of pSer473 AKT after 30 minutes, which is sustained for 48 hours. Total AKT protein signal decreases gradually from 8 hours to 48 hours of treatment^[1].
CCT128930 (PTEN-null U87MG human glioblastoma cells; over a 24-hour time period) results in an increase in G0/G1 phase cells from 43.6% to 64.8% after 24 hours of treatment^[1].
CCT128930 (0-10 μM; 24 hours) increases, but not inhibites, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 (0-20 μM; 24 hours) inhibits cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. CCT128930 (20 μM) triggers cell apoptosis with activation of caspase-3, caspase-9, and PARP. CCT128930 (0-20 μM; 24 hours) increases phosphorylation of ERK and JNK in HepG2 cells. CCT128930 (0-20 μM; 24 hours) activates DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2^[2].
In Vivo: CCT128930 (25 or 40 mg/kg; i.p. daily or twice daily for 5 days) shows antitumor activities in U87MG and BT474 human breast cancer xenografts^[1].
Summary of the pharmacokinetic parameters of CCT128930 (25 mg/kg) in CrTacNCr-Fox1nu mice^[1]

Tissue	Route	T1/2 (h)	Tmax (h)	Cmax (μM)	Vss (L)	Cl (L/h)	AUC0-∞ (µMh)	Bioavailability (%)
Plasma	i.v.	0.95	0.083	6.36	0.25	0.325	4.62	100
Plasma	i.p.	2.33	0.5	1.28	N/A	0.372	1.33	28.8
Tumor	i.p.	3.89	1	8.02	N/A	0.06*	25.8	N/A
Plasma	p.o.	0.57	0.5	0.432	N/A	0.317	0.392	8.5

^*Apparent clearance.