Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 13, 2011, Pages 4036-4040

  Liu, Qingsong ^a,b   Wang, Jinhua ^a,b   Kang, Seong A ^c,d   Thoreen, Carson C ^a,b   Hur, Wooyoung ^a,b   Choi, Hwan Geun ^a,b   Waller, David L ^a,b   Sim, Taebo ^a,b   Sabatini, David M ^c,d   Gray, Nathanael S ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^d MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

mTOR; PI3K; Torin1

Indexed keywords

BENZONAPHTHYRIDINONE DERIVATIVE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; TORIN 1; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DEVELOPMENT; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG SELECTIVITY; DRUG STRUCTURE; IN VIVO STUDY; LIVER MICROSOME; MAXIMUM PLASMA CONCENTRATION; MICROSOME; MOUSE; NONHUMAN;

ANIMALS; CELLS, CULTURED; DRUG DISCOVERY; DRUG STABILITY; ENZYME ACTIVATION; ENZYME INHIBITORS; INHIBITORY CONCENTRATION 50; MICE; MICROSOMES, LIVER; MOLECULAR STRUCTURE; NAPHTHYRIDINES; TOR SERINE-THREONINE KINASES;

EID: 80955181164     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.04.129     Document Type: Article

References (22)

1. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Nat. Rev. Drug Disc. 2009, 8, 627.
2. Shor, B.; Gibbons, J. J.; Abraham, R. T.; Yu, K. Cell Cycle 2009, 8, 3831.
3. Meric-Bernstam, F.; Gonzalez-Angulo, A. M. J. Clin. Oncol. 2009, 27, 2278.
4. Liu, Q.; Thoreen, C. C.; Wang, J.; Sabatini, D. M.; Gray, N. S. Drug Discovery Today: Ther. Strateg. 2009, 6, 47.
5. Guertin, D. A.; Sabatini, D. M. Cancer Cell 2007, 12, 9.
6. Sarbassov, D. D.; Ali, S. M.; Sengupta, S.; Sheen, J. H.; Hsu, P. P.; Bagley, A. F.; Markhard, A. L.; Sabatini, D. M. Mol. Cell 2006, 22, 159.
7. Thoreen, C. C.; Kang, S. A.; Chang, J. W.; Liu, Q.; Zhang, J.; Gao, Y.; Reichling, L. J.; Sim, T.; Sabatini, D. M.; Gray, N. S. J. Biol. Chem. 2009, 284, 8023.
8. Carracedo, A.; Pandolfi, P. P. Oncogene 2008, 27, 5527.
9. Abraham, R. T. DNA Repair 2004, 3, 883.
10. Park, S.; Chapuis, N.; Bardet, V.; Tamburini, J.; Gallay, N.; Willems, L.; Knight, Z. A.; Shokat, K. M.; Azar, N.; Viguie, F.; Ifrah, N.; Dreyfus, F.; Mayeux, P.; Lacombe, C.; Bouscary, D. Leukemia 2008, 22, 1698.
11. Maira, S. M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Mol. Cancer Ther. 2008, 7, 1851.
12. Liu, Q.; Chang, J. W.; Wang, J.; Kang, S. A.; Thoreen, C. C.; Markhard, A.; Hur, W.; Zhang, J.; Sim, T.; Sabatini, D. M.; Gray, N. S. J. Med. Chem. 2010, 53, 7146.
13. Feldman, M. E.; Apsel, B.; Uotila, A.; Loewith, R.; Knight, Z. A.; Ruggero, D.; Shokat, K. M. PLoS Biol. 2009, 7, e38.
14. Garcia-Martinez, J. M.; Moran, J.; Clarke, R. G.; Gray, A.; Cosulich, S. C.; Chresta, C. M.; Alessi, D. R. Biochem. J. 2009, 421, 29.
15. Yu, K.; Toral-Barza, L.; Shi, C.; Zhang, W. G.; Lucas, J.; Shor, B.; Kim, J.; Verheijen, J.; Curran, K.; Malwitz, D. J.; Cole, D. C.; Ellingboe, J.; Ayral-Kaloustian, S.; Mansour, T. S.; Gibbons, J. J.; Abraham, R. T.; Nowak, P.; Zask, A. Cancer Res. 2009, 69, 6232.
16. Barr, S.; Russo, S.; Buck, E.; Epstein, D.; Miglarese, M. AACR 101st Annual meeting, Washington DC, April, 2010, 1632.
17. Chresta, C. M.; Davies, B. R.; Hickson, I.; Harding, T.; Cosulich, S.; Critchlow, S. E.; Vincent, J. P.; Ellston, R.; Jones, D.; Sini, P.; James, D.; Howard, Z.; Dudley, P.; Hughes, G.; Smith, L.; Maguire, S.; Hummersone, M.; Malagu, K.; Menear, K.; Jenkins, R.; Jacobsen, M.; Smith, G. C.; Guichard, S.; Pass, M. Cancer Res. 2010, 70, 288.
18. Menear, K. A.; Gomez, S.; Malagu, K.; Bailey, C.; Blackburn, K.; Cockcroft, X. L.; Ewen, S.; Fundo, A.; Le Gall, A.; Hermann, G.; Sebastian, L.; Sunose, M.; Presnot, T.; Torode, E.; Hickson, I.; Martin, N. M.; Smith, G. C.; Pike, K. G. Bioorg. Med. Chem. Lett. 2009, 19, 5898.
19. Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Toral-Barza, L.; Hollander, I.; Lucas, J.; Yu, K.; Zask, A. Bioorg. Med. Chem. Lett. 2009, 19, 6830.
20. Yu, K.; Shi, C.; Toral-Barza, L.; Lucas, J.; Shor, B.; Kim, J. E.; Zhang, W. G.; Mahoney, R.; Gaydos, C.; Tardio, L.; Kim, S. K.; Conant, R.; Curran, K.; Kaplan, J.; Verheijen, J.; Ayral-Kaloustian, S.; Mansour, T. S.; Abraham, R. T.; Zask, A.; Gibbons, J. J. Cancer Res. 2010, 70, 621.
21. Verheijen, J. C.; Yu, K.; Toral-Barza, L.; Hollander, I.; Zask, A. Bioorg. Med. Chem. Lett. 2010, 20, 375.
22. Malagu, K.; Duggan, H.; Menear, K.; Hummersone, M.; Gomez, S.; Bailey, C.; Edwards, P.; Drzewiecki, J.; Leroux, F.; Quesada, M. J.; Hermann, G.; Maine, S.; Molyneaux, C. A.; Le Gall, A.; Pullen, J.; Hickson, I.; Smith, L.; Maguire, S.; Martin, N.; Smith, G.; Pass, M. Bioorg. Med. Chem. Lett. 2009, 19, 5950.