Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR

A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.

Graphical abstractThe discovery and optimisation of a novel series of inhibitors of mTOR kinase are described. Compound 15 has low nanomolar potency against mTOR kinase and is highly selective relative to PI3Kα.Figure optionsDownload full-size imageDownload as PowerPoint slide