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Issue 2, 2010
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Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design

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Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Kα or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway, e.g. PI3K, AKT, mTOR, offers great potential for the treatment of cancer. Lead optimization through integration of structure based drug design (SBDD) and physical properties-based optimization (PPBO) led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502, 1) that demonstrated potent in vitro inhibitory activity against both PI3K and mTOR, excellent kinase selectivity, good ADMET, and robust in vivo efficacy in a mouse xenograft tumor growth model. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.

Graphical abstract: Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design

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Publication details

The article was received on 05 Jun 2010, accepted on 23 Jun 2010 and first published on 23 Jul 2010


Article type: Concise Article
DOI: 10.1039/C0MD00072H
Citation: Med. Chem. Commun., 2010,1, 139-144
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    Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design

    H. Cheng, S. Bagrodia, S. Bailey, M. Edwards, J. Hoffman, Q. Hu, R. Kania, D. R. Knighton, M. A. Marx, S. Ninkovic, S. Sun and E. Zhang, Med. Chem. Commun., 2010, 1, 139
    DOI: 10.1039/C0MD00072H

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