CCT128930

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

CCT128930 是一种有效的、选择性的、ATP 竞争性 AKT 抑制剂，IC50 为 6 nM (AKT2)。

CCT128930 is a potent, selective, ATP-competitive AKT inhibitor with IC50 of 6 nM (AKT2), 28-fold selectivity over the closely related PKA; also exhibits 20-fold selectivity over p70S6K (IC50=120 nM); shows growth inhibition for U87MG human glioblastoma cells (IC50=6.3 uM), for LNCaP human prostate cancer cells (IC50=0.35 uM), and for PC3 human prostate cancer cells (IC50=1.9 uM) consistent with AKT pathway blockade; blocks the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo; demonstrates antitumor activity in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts.

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.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.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.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.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. 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.

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.Summary of the pharmacokinetic parameters of CCT128930 (25 mg/kg) in CrTacNCr-Fox1nu mice.Apparent clearance. Animal Model:6-8 weeks old female CrTacNCr-Fox1nu mice Dosage:25 mg/kg (U87MG human glioblastoma xenografts) or 40 mg/kg (BT474 human breast cancer xenografts)Administration:i.p. daily for 5 days (U87MG human glioblastoma xenografts); i.p. twice daily for 5 days (BT474 human breast cancer xenografts)Result:Giving a treated:control (T/C) ratio on day 12 of 48%. There was no weight loss associated with this regime in U87MG human glioblastoma xenografts.

CCT 128930 | CCT-128930

Cytoskeleton/Cell Adhesion Molecules

Akt

Akt2 , p70 S6K , PKA

Cancer

——

885499-61-6

341.8

C18H20ClN5

>98% (HPLC)

10 mM in DMSO

NC1(CC2=CC=C(Cl)C=C2)CCN(C3=C4C(NC=C4)=NC=N3)CC1

4-Piperidinamine, 4-[(4-chlorophenyl)methyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-

(-20℃)

With Ice Pack

≥ 2 years