Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase.
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kgamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.
Nowak
Pawel
P
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. nowakp@wyeth.com
Cole
Derek C
DC
Brooijmans
Natasja
N
Bursavich
Matthew G
MG
Curran
Kevin J
KJ
Ellingboe
John W
JW
Gibbons
James J
JJ
Hollander
Irwin
I
Hu
YongBo
Y
Kaplan
Joshua
J
Malwitz
David J
DJ
Toral-Barza
Lourdes
L
Verheijen
Jeroen C
JC
Zask
Arie
A
Zhang
Wei-Guo
WG
Yu
Ker
K
D001667:Binding, Competitive; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases