Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 4, 2010, Pages 1440-1444

  Curran, Kevin J ^a   Verheijen, Jeroen C ^a   Kaplan, Joshua ^a   Richard, David J ^a   Toral Barza, Lourdes ^a   Hollander, Irwin ^a   Lucas, Judy ^a   Ayral Kaloustian, Semiramis ^a   Yu, Ker ^a   Zask, Arie ^a  

^a WYETH RESEARCH   (United States)

Author keywords

Kinase; mTOR; P13K

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PROTEIN KINASE B; PYRAZOLOPYRIMIDINE DERIVATIVE; S6 KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DRUG POTENCY; DRUG STRUCTURE; HUMAN; HUMAN CELL; IC 50; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; SUZUKI REACTION;

ADENOSINE TRIPHOSPHATE; ADMINISTRATION, ORAL; ANIMALS; BINDING, COMPETITIVE; DRUG STABILITY; HUMANS; INHIBITORY CONCENTRATION 50; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; MICROSOMES; MOLECULAR STRUCTURE; PROTEIN-SERINE-THREONINE KINASES; PYRAZOLES; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; XENOGRAFT MODEL ANTITUMOR ASSAYS;

MAMMALIA;

EID: 75449120554     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.12.086     Document Type: Article

References (18)

1. For a recent review of mTOR inhibitors in oncology see: Verheijen, J.C.; Yu, K.; Zask, A. Ann. Rep. Med. Chem., John E. Macor, editor, 2008, 43, 189.
2. Sarbassov D.D., Ali S.M., Kim D.-H., Guertin D.A., Latek R.R., Erdjument-Bromage H., Tempst P., and Sabatini D.M. Curr. Biol. 14 (2004) 1296
3. Sarbassov D.D., Guertin D.A., Ali S.M., and Sabatini D.M. Science 307 (2005) 1098
4. Hresko R.C., and Mueckler M. J. Biol. Chem. 280 (2005) 40406
5. Shi Y., Yan H., Frost P., Gera J., and Lichtensein A. Mol. Cancer Ther. 4 (2005) 1533
6. 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., and Zask A. Cancer Res. 69 (2009) 6232
7. Zask A., Verheijen J.C., Curran K., Kaplan J., Richard D.J., Nowak P., Malwitz D.J., Brooijmans N., Bard J., Svenson K., Lucas J., Toral-Barza L., Zhang W.-G., Hollander I., Gibbons J.J., Abraham R.T., Ayral-Kaloustian S., Mansour T.S., and Yu K. J. Med. Chem. 52 (2009) 5013
8. Zask A., Kaplan J., Verheijen J., Richard D.J., Curran K., Brooijmans N., Bennett E., Toral-Barza L., Hollander I., Ayral-Kaloustian S., and Yu K. J. Med. Chem. (2009) 10.1021/jm901415x
9. Verheijen J.C., Richard D.J., Curran K., Kaplan J., Lefever M., Nowak P., Malwitz D.J., Brooijmans N., Toral-Barza L., Zhang W.-G., Hollander I., Ayral-Kaloustian S., Mansour T.S., Yu K., and Zask A. J. Med. Chem. (2009) 10.1021/jm9013828
10. Richard D.J., Verheijen J.C., Curran K., Kaplan J., Brooijmans N., Toral-Barza L., Hollander I., Yu K., and Zask A. Bioorg. Med. Chem. Lett. 19 (2009) 6830
11. Kaplan, J.; Verheijen, J. C.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Yu, K.; Zask, A. Bioorg. Med. Chem. Lett. doi: 10.1016/j.bmcl.2009.11.050.
12. Zask, A.; Kaplan, J. A.; Verheijen, J. C.; Curran, K. J.; Richard, D. J.; Ayral-Kaloustian, S. WO Patent Appl. 2009052145A1, 2009.
13. Braun J., and Seemann J. Chem. Ber. 56 (1923) 1840
14. Biological methods for determination of mTOR inhibition are described in:. Toral-Barza L., Zhang W.G., Lamison C., Larocque J., Gibbons J., and Yu K. Biochem. Biophys. Res. Commun. 332 (2005) 304
15. Biological methods for determination of inhibition of cellular proliferation are described in:. Yu K., Toral-Barza L., Discafani C., Zhang W.G., Skotnicki J., Frost P., and Gibbons J. Endocr. Relat. Cancer 8 (2001) 249
16. Biological methods for determination of PI3K inhibition are described in:. Zask A., Kaplan J., Toral-Barza L., Hollander I., Young M., Tischler M., Gaydos C., Cinque M., Lucas J., and Yu K. J. Med. Chem. 51 (2008) 1319
17. Biological methods for determination of microsomal stability are described in:. Tsou H.-R., Liu X., Birnberg G., Kaplan J., Otteng M., Tran T., Kutterer K., Tang Z., Suayan R., Zask A., Ravi M., Bretz A., Grillo M., McGinnis J.P., Rabindran S.K., Ayral-Kaloustian S., and Mansour T.S. J. Med. Chem. 52 (2009) 2289
18. For full biological characterization of 8a see: Yu, K.; Shi C.; Toral-Barza, L.; Lucas, J.; Shor, B.; Kim, J.; Zhang, W.-G.; Mahoney, R.; Gaydos, C.; Tardio, L.; Kim, K.; Curran, K. J.; Ayral-Kaloustian, S.; Mansour, T.S.; Abraham, R. T.; Zask, A.; Gibbons, J. J. Cancer Res., unpublished results.