thienopyrimidine and pyrazolopyridine

mTOR is a serine-threonine kinase that plays a key role in the regulation of cellular growth. The mTOR pathway consists of two distinct complexes: mTOR/Raptor (mTORC1) and mTOR/Rictor (mTORC2). In response to changes in the levels of insulin, nutrients and energy supply, signaling through these complexes affects a variety of processes, including protein translation and cell proliferation. The efficacy of derivatives of the natural product rapamycin (sirolimus), which functions as an allosteric inhibitor of mTORC1, has validated mTOR inhibition as an anticancer treatment. More recently, extensive efforts have been focused on the discovery of ATP-competitive inhibitors of mTOR that would inhibit both mTORC1 and mTORC2 and may provide additional clinical benefit. This review provides a summary of recent research efforts in this field, focusing on mTOR inhibitors that are selective for mTOR over the related lipid kinase PI3K.

Topics: Adenosine Triphosphate; Animals; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Binding, Competitive; Computer Simulation; Drug Discovery; Intracellular Signaling Peptides and Proteins; Mice; Microsomes; Models, Molecular; Morpholines; Protein Serine-Threonine Kinases; Pyrans; Pyrazoles; Pyridines; Pyrimidines; TOR Serine-Threonine Kinases