AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth

The serine/threonine kinase AKT plays a pivotal role in signal transduction occasions involved with malignant transformation and chemoresistance and it is a beautiful target to add mass to cancer therapeutics. Fragment-based lead discovery, coupled with structure-based drug design, has lately identified AT7867 like a novel and potent inhibitor of both AKT and also the downstream kinase p70 S6 kinase (p70S6K) as well as of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at your bodies cells, as measured by inhibition of GSK3beta and S6 ribosomal protein phosphorylation, as well as causes growth inhibition in a variety of human cancer cell lines like a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic rodents implanted using the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations produced in vitro. These doses of AT7867 also led to inhibition of human tumor development in PTEN-deficient xenograft models. These data claim that the novel technique of AKT and p70S6K blockade might have therapeutic value and supports further look at AT7867 like a single-agent anticancer strategy.