Structure-Based Discovery of Novel Inhibitors of Protein Kinase
Abstract
AKT/PKB is a serine/threonine kinase. Inappropriate activation of P13/AKT has been associated with the development of cancer cells, their metastasis and drug resistance. Hence, potent and selective inhibitors targeting AKT are potentially promising drug candidates for the treatment of cancer cells with high-levels of AKT activity. We used a bioinformatics approach to search for AKT inhibitors, based on the correlation analysis between phosphor-Serine 473- AKT or PTEN expression level and the antiproliferation data of NCI small molecule compounds against NCI 60 cancer cell lines, then the candidate compounds were subject to AKT kinase assay. One lead compound API-59 was identified. API- 59 inhibit only AKT activity, does not inhibit phosphor-specific MAP kinase or PT 3 kinase. API-59 also inhibits heregulin-induced AKT activity in MCF-7 breast cancer cells. The AKT inhibitory effect of API-59 can be reversed by increased concentration of ATP. API-59 inhibits the cell proliferation, and induces apoptosis of MDA-453 breast cancer cells with high-levels of AKT activity, only shows a minimal activity in wild-type NIH-3T3 cells that do not overexpress AKT. These data suggest our bioinformatics-based approach is effective in discovery of potent and selective small molecule inhibitors that block AKT kinase activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA424718
Entities
People
- Dejun Yang
Organizations
- University of Michigan