Targeting the mTOR kinase domain: the second generation of mTOR inhibitors

• Published in: Drug discovery today Vol. 16; no. 7; pp. 325 - 331
• Main Authors: Zhang, Yan-Jie, Duan, Yanwen, Zheng, X.F. Steven
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-04-2011; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Clinical Trials as Topic; General pharmacology; Humans; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Signal Transduction - drug effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Target; Pharmaceutical technology; Targeting; Enzyme; Kinase; Transferases; Mammalian target of rapamycin; mTOR inhibitor
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2011.02.008

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.