mTOR Inhibition for Cancer Therapy: Past, Present and Future by Monica Mita, Alain Mita, Eric K. Rowinsky

By Monica Mita, Alain Mita, Eric K. Rowinsky

This publication describes the demanding situations considering constructing mTOR inhibitors for melanoma remedy, beginning with an in-depth exam in their molecular mechanism of motion, with emphasis at the classification side-effects, efficacy and mechanisms of resistance, in addition to on promising novel instructions for his or her improvement, together with novel compounds and rational combos with different anti-neoplastic medicines.

Over the final 10 years, inhibitors of mTOR have emerged as an immense type of anticancer medicinal drugs. rapamycin analogs are at the moment licensed for the remedy of renal mobile carcinoma, and it truly is envisioned number of different tumor varieties may gain advantage from mTOR inhibition, with various medical trials (including pivotal registration trials) already underway. Second-generation small-molecule inhibitors of the pathway have additionally proven promise when it comes to their more advantageous tolerability and efficacy and are present process wide scientific evaluate, with an envisioned 30+ compounds at the moment less than evaluate.

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Additional resources for mTOR Inhibition for Cancer Therapy: Past, Present and Future

Example text

94. Maira SM, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7(7):1851–63. 95. Benjamin D, et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011;10(11):868–80. 96. Bendell JC, et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors.

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101. 22. Jacinto E, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125–37. 23. Frias MA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16(18):1865–70. 24. Pearce LR, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2.

11. Hara K, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89. 12. Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol. 2002;12(8):632–9. 13. Sancak Y, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15. 14. Wang L, et al. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282(27):20036–44.

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