Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.
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.
Zask
Arie
A
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. zaska@wyeth.com
Kaplan
Joshua
J
Verheijen
Jeroen C
JC
Richard
David J
DJ
Curran
Kevin
K
Brooijmans
Natasja
N
Bennett
Eric M
EM
Toral-Barza
Lourdes
L
Hollander
Irwin
I
Ayral-Kaloustian
Semiramis
S
Yu
Ker
K
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
D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases