title: Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.
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.
authors.affiliation: Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. zaska@wyeth.com
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Verheijen
authors.forename: David J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Kevin
authors.initials: K
authors.lastname: Curran
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
chemical_list: D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases