Recent advances in the development of selective, ATP-competitive inhibitors of mTOR.
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.
Richard
David J
DJ
Pfizer Global Research, Pearl River, NY 10965, USA. david.j.richard@pfizer.com
Verheijen
Jeroen C
JC
Zask
Arie
A
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C118531:pyrazolopyridine; C476003:thienopyrimidine; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus