Search

A series of novel, highly potent, selective, and ATP-competitivemammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepinescaffold have been identified. Lead optimization resulted in the discoveryof inhibitors with low nanomolar activity and greater than 1000-foldselectivity over the closely related PI3K kinases. Compound 28(XL388) inhibited cellular phosphorylation of mTOR complex1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates.Furthermore, this compound displayed good pharmacokinetics and oralexposure in multiple species with moderate bioavailability. Oral administrationof compound 28to athymic nude mice implanted with humantumor xenografts afforded significant and dose-dependent antitumoractivity. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3-kinases (PI3Ks) have been linkedto an extraordinarilydiversified group of cellular functions making these enzymes compellingtargets for the treatment of disease. A large body of evidence haslinked PI3Kγ to the modulation of autoimmune and inflammatoryprocesses making it an intriguing target for drug discovery. Our high-throughputscreening (HTS) campaign revealed two hits that were nominated forfurther optimization studies. The in vitro activity of the first HTShit, designated as the sulfonylpiperazine scaffold, was optimizedutilizing structure-based design. However, nonoptimal pharmacokineticproperties precluded this series from further studies. An overlayof the X-ray structures of the sulfonylpiperazine scaffold and thesecond HTS hit within their complexes with PI3Kγ revealed ahigh degree of overlap. This feature was utilized to design a seriesof hybrid analogues including advanced leads such as 31with desirable potency, selectivity, and oral bioavailability. [ABSTRACT FROM AUTHOR]