CCT128930

CCT128930 is a potent, selective, novel and ATP-competitive inhibitor for AKT2 (IC50= 6 nM). It also has 28-fold and 20-fold selectivity over PKA kinase (IC50= 168 nM) and p70S6K (IC50= 120 nM), respectively.

Akt (protein kinase B) is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.

In multi tumor cell line, CCT128930 showed antiproliferative effect and blocked the phosphorylation of various Akt substrates. In PTEN-null human glioblastoma cells (U87MG), CCT128930 treatment led to a G1 arrest associated with Akt pathway suppression. [1]

In U87MG tumor xenografts, CCT128930 inhibited the phosphorylation of Akt downstream biomarkers. In U87MG, HER-2 positive and IK3CA-mutant BT474 human breast cancer xenografts, antitumor activity were recorded as tumor volume decreased. CCT128930-treated mouse whisker folliciles in vivo and human hair follicles treated ex vivo exerted prominent reduction in pThr246 PRAS40. [1]

Reference:
1. Yap TA, Walton MI, Hunter LJ et al.  Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol Cancer Ther. 2011 Feb;10(2):360-71.

CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition.[Pubmed:24793486]

Biochimie. 2014 Aug;103:118-25.

PI3K/Akt/mTOR pathway plays an important role in tumor progression and anti-cancer drug resistance. The aim of the present study is to determine the antitumor effect of CCT128930, a novel small molecule inhibitor of Akt, in the HepG2 hepatoma cancer cells. Our results showed that at low concentrations, CCT128930 increased, but not inhibited, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 inhibited cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. A higher dose (20 muM) of CCT128930 triggered cell apoptosis with activation of caspase-3, caspase-9, and PARP. Treatment with CCT128930 increased phosphorylation of ERK and JNK in HepG2 cells. CCT128930 activated DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2. Upon exposure to CCT128930 at a higher concentration, HepG2 cells exhibited autophagy was accompanied by an increase the levels of LC3-II and Beclin-1. Blocking autophagy using chloroquine magnified CCT128930-induced apoptotic cell death and the phosphorylation of H2AX. The results in this study have advanced our current understandings of the anti-cancer mechanisms of CCT128930 in cancer cells.

Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930.[Pubmed:21191045]

Mol Cancer Ther. 2011 Feb;10(2):360-71.

AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G(1) arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials.

CCT128930 is a potent and selective inhibitor of Akt2 (IC50 6 nM) with 28-fold selectivity over the closely related PKA kinase (IC50 168 nM), as well as 20-fold selectivity over p70S6K (IC50 120 nM).

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