Morpholine Derivatives Greatly Enhance the Selectivity of Mammalian Target of Rapamycin (mTOR) Inhibitors
作者
ZASK ARIE; KAPLAN JOSHUA; VERHEIJEN JEROEN C; RICHARD DAVID J; CURRAN KEVIN; BROOIJMANS NATASJA; BENNETT ERIC M; TORALBARZA LOURDES; HOLLANDER IRWIN; AYRALKALOUSTIAN SEMIRAMIS; YU KER
[摘要]：Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC50 values and up to 26000-fold selectivity versus PI3K alpha 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 (Phe961 Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
