title: Development of ATP-competitive mTOR inhibitors.
abstract: The mammalian Target of Rapamycin (mTOR)-mediated signaling transduction pathway has been observed to be deregulated in a wide variety of cancer and metabolic diseases. Despite extensive clinical development efforts, the well-known allosteric mTOR inhibitor rapamycin and structurally related rapalogs have failed to show significant single-agent antitumor efficacy in most types of cancer. This limited clinical success may be due to the inability of the rapalogs to maintain a complete blockade mTOR-mediated signaling. Therefore, numerous efforts have been initiated to develop ATP-competitive mTOR inhibitors that would block both mTORC1 and mTORC2 complex activity. Here, we describe our experimental approaches to develop Torin1 using a medium throughput cell-based screening assay and structure-guided drug design.
authors: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
authors: Qingsong
authors: Q
authors: Liu
authors: Seong A
authors: SA
authors: Kang
authors: Carson C
authors: CC
authors: Thoreen
authors: Wooyoung
authors: W
authors: Hur
authors: Jinhua
authors: J
authors: Wang
authors: Jae Won
authors: JW
authors: Chang
authors: Andrew
authors: A
authors: Markhard
authors: Jianming
authors: J
authors: Zhang
authors: Taebo
authors: T
authors: Sim
authors: David M
authors: DM
authors: Sabatini
authors: Nathanael S
authors: NS
authors: Gray
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D011506:Proteins; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus