학술논문
Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor
Document Type
Article
Author
Heffron, Timothy P.; Berry, Megan; Castanedo, Georgette; Chang, Christine; Chuckowree, Irina; Dotson, Jennafer; Folkes, Adrian; Gunzner, Janet; Lesnick, John D.; Lewis, Cristina; Mathieu, Simon; Nonomiya, Jim; Olivero, Alan; Pang, Jodie; Peterson, David; Salphati, Laurent; Sampath, Deepak; Sideris, Steve; Sutherlin, Daniel P.; Tsui, Vickie
Source
Subject
*PHOSPHOINOSITIDES
*ENZYME inhibitors
*PYRIMIDINES
*METHYL groups
*MELTING points
*ENZYME kinetics
*ADDITION reactions
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Language
ISSN
0960-894X
Abstract
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. [Copyright &y& Elsevier]