Mammalian Target of Rapamycin ( mTOR ) Inhibitor for Treatment of Cancer

The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(50): 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1.

[1]  D. Sabatini,et al.  Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. , 2010, Journal of medicinal chemistry.

[2]  D. Epstein,et al.  Abstract 1632: Co-targeting mTOR and IGF-1R/IR results in synergistic activity against a broad array of tumor cell lines, independent ofKRASmutation status , 2010 .

[3]  R. Abraham,et al.  Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. , 2010, Cancer research.

[4]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[5]  Lisa L. Smith,et al.  AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. , 2010, Cancer research.

[6]  L. Toral-Barza,et al.  Incorporation of water-solubilizing groups in pyrazolopyrimidine mTOR inhibitors: discovery of highly potent and selective analogs with improved human microsomal stability. , 2009, Bioorganic & medicinal chemistry letters.

[7]  R. Abraham,et al.  Targeting mTOR globally in cancer: Thinking beyond rapamycin , 2009, Cell cycle.

[8]  I. Hickson,et al.  Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR. , 2009, Bioorganic & medicinal chemistry letters.

[9]  Kevin Curran,et al.  Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. , 2009, Cancer research.

[10]  Funda Meric-Bernstam,et al.  Targeting the mTOR signaling network for cancer therapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[12]  C. Chresta,et al.  Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) , 2009, The Biochemical journal.

[13]  H. Lane,et al.  Optimal targeting of the mTORC1 kinase in human cancer. , 2009, Current opinion in cell biology.

[14]  D. Sabatini,et al.  An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1* , 2009, Journal of Biological Chemistry.

[15]  Robbie Loewith,et al.  Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 , 2009, PLoS biology.

[16]  David M Sabatini,et al.  Defining the role of mTOR in cancer. , 2007, Cancer cell.

[17]  L. Helman,et al.  Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism , 2007, Oncogene.

[18]  D. Sabatini.  mTOR and cancer: insights into a complex relationship , 2006, Nature Reviews Cancer.

[19]  G. Kroemer,et al.  Current development of mTOR inhibitors as anticancer agents , 2006, Nature Reviews Drug Discovery.

[20]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[21]  D. Sabatini,et al.  Growing roles for the mTOR pathway. , 2005, Current opinion in cell biology.

[22]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[23]  R. Loewith,et al.  Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive , 2004, Nature Cell Biology.

[24]  Robert T Abraham,et al.  PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. , 2004, DNA repair.

[25]  D O Thompson,et al.  Cyclodextrins--enabling excipients: their present and future use in pharmaceuticals. , 1997, Critical reviews in therapeutic drug carrier systems.