title: Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which is the key component of two distinct signaling complexes in cells; these complexes are the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). Given the importance of these complexes in cellular growth, survival, motility, proliferation, protein synthesis and transcription, it is not surprising that they are impacted in multiple types of cancer. Studies on a number of ATP-competitive mTOR inhibitors have suggested that these inhibitors have a therapeutic superiority to rapalogs (rapamycin analogs) in a number of cancers.
  
  
  METHODS
  This review provides insight into the binding of mTOR inhibitors with the ATP-binding site, for the benefit of future mTOR inhibitor design and discovery. The authors, furthermore, deduce that a hypothetical binding mode is from docking studies, co-crystal structures and the structure-activity relationships (SARs). The authors also highlight the preclinical and clinical development of hit/lead compounds, and the selectivity for representative mTOR inhibitors.
  
  
  CONCLUSIONS
  The structural analysis of mTOR is hampered by its large size and complexity. Further exploration of mTOR inhibitors may therefore require the combination of structure-based drug design (SBDD, based on the mTOR homology models), fragment-based drug design (FBDD) and analog synthesis. Recent studies suggested that the global inhibition of PI3Ks may be harmful to organisms. Therefore, the future discovery of dual mTOR/PI3K inhibitors needs to ensure that inhibitors are both efficacious and have reduced adverse effects.
authors.affiliation: Zhejiang University, College of Pharmaceutical Sciences, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Hangzhou 310058, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lv
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus