Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.

Graphical abstractEfforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the evaluation of tetrasubstituted thienopyrimidines. These molecules generally have reduced in vivo clearance relative to the trisubstituted thienopyrimidines culminating in the identification of GNE-477 (8).Figure optionsDownload full-size imageDownload as PowerPoint slide