new potent and high selective mTOR inhibitor with better stability of mouse liver microsome stability was discovered by Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School. They report this discovery on the Bioorganic & Medicinal Chemistry Letters. The researchers do not name this compound and just take â€the compound 10†as the name of this mTOR inhibitor. Starting from the mTOR inhibitor Torin1, this compound shows improved mouse microsome stability and good pharmacokinetic properties. Torin1 is a potent and selective mTOR inhibitor. Torin1 can inhibit mTORC1 and mTORC2 with IC50 between 2nM and 10nM.(In this poster, I will focus on the new inhbitor,the compound10. I will provide more information about Torin1 because it is a important mTOR inhibitor which is discovered in recent years.) Torin 1, a mTOR inhibitor Now I provide the structure of â€compound10â€. compound10 ,a new mTOR inhibitor We can compare compound10 with Torin1, and we can know that researchers, starting from Torin1, replace the metabolically labile 4-amino-phenylpiperazine moiety with a biphenylsystem resulting in a better mouse microsome stability mTOR inhibitor. There is some data I collect from the article which make me believe that the compound 1o is with good pharmacokinetic properties and we can pay more attention to this series mTOR inhibitors. IC50 value of compound10: Kinase symbol IC50 (nM) PI4K-alpha >10000 PI4K-beta 3440 PI3K-C2alpha 1110 PI3K-C2beta 437 hVPS34 170 p110alpha/p85alpha 922 p110delta/p85alpha 1170 p110-gamma 1170 mTOR 3.01 Data of Mouse microsome stability and CYP450 inhibition results: Compound Mouse microsome stability (min) NADPH dependent CYP3A4 % inhibition (10 uM) CYP2D6 % inhibition (10 uM) Torin1 1.3 N ND ND compound 10 46 Y 61 51 The compound 10 with drug-like properties is an important compound which we should pay attention to. There are some experiment result: Researchers compare Torin1 to PI-103. After reading this experiment result, we can know that Torin1 is a high selective mTOR inhibitor. The selection of Torin1 of mTOR is higher than PI-103, and the potency of Torin1 in cell is better than PI-103. I also conclude the EC50 of Torin1. The structure of Torin1: Torin 1, a mTOR inhibitor I provide the western blotting result of Torin1 to prove the inhibition of mTORC1 and mTORC2. The inhibtion of mTORC1: The inhibition of mTORC2: From those 2 results, we know that Torin1 inhibit mTORC1 and mTORC2 with IC50 value of 2-10nM. Torin1 is a ATP-competitive inhibitor. We can know this from another western blotting result. We can know that the inhibition of the certain concentration Torin1 become less, as the concentration of ATP grows higher. To konw the potency of Torin1, researchers compare Torin1 to NVP-BEZ235 and PI-103. Reference: (1)Liu, Q., J. Wang, et al. (2011). â€Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability.†Bioorg Med Chem Lett 21(13): 4036-4040. (2) Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., and Gray, N. S. (2009) J Biol Chem. (3) Guertin, D. A., and Sabatini, D. M. (2007) Cancer Cell 12, 9-22.
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