1062159-67-4Relevant academic research and scientific papers
Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase
Nowak, Pawel,Cole, Derek C.,Brooijmans, Natasja,Bursavich, Matthew G.,Curran, Kevin J.,Ellingboe, John W.,Gibbons, James J.,Hollander, Irwin,Hu, YongBo,Kaplan, Joshua,Malwitz, David J.,Toral-Barza, Lourdes,Verheijen, Jeroen C.,Zask, Arie,Zhang, Wei-Guo,Yu, Ker
, p. 7081 - 7089 (2009)
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 PI3Kγ 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 IC50 = 9 nM; PI3Kα 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. 2009 American Chemical Society.
