A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate.
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 (IC(50) 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.
Falasca
M
M
Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute of Cell and Molecular Science, Centre for Diabetes, Inositide Signalling Group, 4 Newark Street, London E1 2AT, UK. m.falasca@qmul.ac.uk
Chiozzotto
D
D
Godage
H Y
HY
Mazzoletti
M
M
Riley
A M
AM
Previdi
S
S
Potter
B V L
BV
Broggini
M
M
Maffucci
T
T
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D016503:Drug Delivery Systems; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
C546965:2-O-benzylinositol 1,3,4,5,6-pentakisphosphate; D000970:Antineoplastic Agents; D007295:Inositol Phosphates; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C013571:inositol pentaphosphate; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases