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Preclinical pharmacology, antitumor activity and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930
Preclinical pharmacology, antitumor activity and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930
- Publication Year :
- 2010
-
Abstract
- 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 G1 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. Mol Cancer Ther; 10(2); 360–71. ©2010 AACR.
- Subjects :
- Male
Cancer Research
Mice, Nude
Antineoplastic Agents
Biology
Pharmacology
Article
Biomarkers, Pharmacological
Mice
In vivo
Cell Line, Tumor
Neoplasms
medicine
Animals
Humans
Pyrroles
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Cell Proliferation
Mice, Inbred BALB C
Cell Cycle
Cancer
medicine.disease
HCT116 Cells
Xenograft Model Antitumor Assays
In vitro
Gene Expression Regulation, Neoplastic
Pyrimidines
Oncology
Cell culture
Phosphorylation
Female
Hair Follicle
Proto-Oncogene Proteins c-akt
Ex vivo
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....2391b9e33067d4b15de78f9959a67d68