Research

A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate


Reference:

Falasca, M., Chiozzotto, D., Godage, H. Y., Mazzoletti, M., Riley, A. M., Previdi, S., Potter, B. V. L., Broggini, M. and Maffucci, T., 2010. A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. British Journal of Cancer, 102 (1), pp. 104-114.

Related documents:

This repository does not currently have the full-text of this item.
You may be able to access a copy if URLs are provided below. (Contact Author)

Official URL:

http://dx.doi.org/10.1038/sj.bjc.6605408

Abstract

BACKGROUND: Owing to its role in cancer, the phosphoinositide 3-kinase (PI3K)/Akt pathway is an attractive target for therapeutic intervention. We previously reported that the inhibition of Akt by inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) results in anti-tumour properties. To further develop this compound we modified its structure to obtain more potent inhibitors of the PI3K/Akt pathway. METHODS: Cell proliferation/survival was determined by cell counting, sulphorhodamine or acridine orange/ethidium bromide assay; Akt activation was determined by western blot analysis. In vivo effect of compounds was tested on PC3 xenografts, whereas in vitro activity on kinases was determined by SelectScreen Kinase Profiling Service. RESULTS: The derivative 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP(5)) is active towards cancer types resistant to InsP(5) in vitro and in vivo. 2-O-Bn-InsP(5) possesses higher pro-apoptotic activity than InsP(5) in sensitive cells and enhances the effect of anti-cancer compounds. 2-O-Bn-InsP(5) specifically inhibits 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro (IC50 in the low nanomolar range) and the PDK1-dependent phosphorylation of Akt in cell lines and excised tumours. It is interesting to note that 2-O-Bn-InsP(5) also inhibits the mammalian target of rapamycin (mTOR) in vitro. CONCLUSIONS: InsP(5) and 2-O-Bn-InsP(5) may represent lead compounds to develop novel inhibitors of the PI3K/Akt pathway (including potential dual PDK1/mTOR inhibitors) and novel potential anti-cancer drugs. British Journal of Cancer (2010) 102, 104-114. doi:10.1038/sj.bjc.6605408 www.bjcancer.com (C) 2010 Cancer Research UK

Details

Item Type Articles
CreatorsFalasca, M., Chiozzotto, D., Godage, H. Y., Mazzoletti, M., Riley, A. M., Previdi, S., Potter, B. V. L., Broggini, M. and Maffucci, T.
DOI10.1038/sj.bjc.6605408
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code17796

Export

Actions (login required)

View Item