title: Targeting the mTOR kinase domain: the second generation of mTOR inhibitors.
abstract: The mTOR signaling pathway is dysregulated in ∼50% of all human malignancies and is a major cancer drug target. Although rapamycin analogs (rapalogs) have shown clinical efficacy in a subset of cancers, they do not fully exploit the antitumor potential of mTOR targeting. Because the mTOR kinase domain is important for rapamycin-sensitive and -insensitive functions, mTOR catalytic inhibitors have been developed recently as the second generation of anti-mTOR agents. Importantly, they have shown marked improvement of antitumor activity in vivo and in vitro. This review will detail the potential therapeutic value and issues of these novel antineoplastic agents, with emphasis placed on those that have already entered clinical trials.
authors.affiliation: Cancer Institute of New Jersey, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Duan
authors.forename: X F Steven
authors.initials: XF
authors.lastname: Zheng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus