Morpholine Derivatives Greatly Enhance the Selectivity of Mammalian Target of Rapamycin (mTOR) Inhibitors
Journal of Medicinal Chemistry2009Vol. 52(24), pp. 7942–7945
Citations Over TimeTop 10% of 2009 papers
Arie Zask, Joshua A. Kaplan, Jeroen C. Verheijen, David J. Richard, Kevin J. Curran, Natasja Brooijmans, Eric M. Bennett, Lourdes Toral‐Barza, Irwin Hollander, Semiramis Ayral‐Kaloustian, Ker Yu
Abstract
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
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