- Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability
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Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life.
- Liu, Qingsong,Wang, Jinhua,Kang, Seong A.,Thoreen, Carson C.,Hur, Wooyoung,Choi, Hwan Geun,Waller, David L.,Sim, Taebo,Sabatini, David M.,Gray, Nathanael S.
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p. 4036 - 4040
(2011/08/06)
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- SOLUBLE MTOR COMPLEXES AND MODULATORS THEREOF
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The present invention relates to small molecule modulators of mTORCl and mT0RC2, syntheses thereof, and intermediates thereto. Such small molecule modulators are useful in the treatment of proliferative diseases (e.g., benign neoplasms, cancers, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases. Novel small molecules are provided that inhibit one or more of mTORCl, mT0RC2, and PI3K-related proteins. Novel methods of providing soluble mTORCl and mT0RC2 complexes are discussed, as well as methods of using the soluble complexes in a high- throughput manner to screen for inhibitory compounds.
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Page/Page column 116
(2010/04/30)
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