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Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor |
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| Authors: | Timothy P. Heffron Megan Berry Georgette Castanedo Christine Chang Irina Chuckowree Jennafer Dotson Adrian Folkes Janet Gunzner John D. Lesnick Cristina Lewis Simon Mathieu Jim Nonomiya Alan Olivero Jodie Pang David Peterson Laurent Salphati Deepak Sampath Steve Sideris Daniel P. Sutherlin Vickie Tsui Bing-yan Zhu |
| Affiliation: | 1. Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Small Molecule Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;3. Biochemical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;4. Piramed Pharma, 957 Buckingham Avenue, Slough, Berkshire SL1 4NL, UK;5. Drug Metabolism and Pharmacokinetics,, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA |
| Abstract: | Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. |
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