Discovery of 2-arylthieno[3,2-d]pyrimidines containing 8-oxa-3-azabi-cyclo[3.2.1]octane in the 4-position as potent inhibitors of mTOR with selectivity over PI3K

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 1, 2010, Pages 375-379

  Verheijen, Jeroen C ^a   Yu, Ker ^a   Toral Barza, Lourdes ^a   Hollander, Irwin ^a   Zask, Arie ^a  

^a WYETH RESEARCH   (United States)

Author keywords

Cancer; Kinase; mTOR; Oncology; PI3K

Indexed keywords

2 (4 UREIDOPHENYL) THIENOPYRIMIDINE DERIVATIVE; 2 ARYLTHIENO[3,2 D]PYRIMIDINE DERIVATIVE; 8 OXA 3 AZABIAZABICYCLO[3.2.1]OCTANE; HETEROCYCLIC COMPOUND; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; UNCLASSIFIED DRUG;

ARTICLE; CELL ACTIVITY; CELL PROLIFERATION; CHEMICAL REACTION; DRUG SELECTIVITY; DRUG STRUCTURE; HUMAN; HUMAN CELL; IC 50; STRUCTURE ACTIVITY RELATION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; CELL LINE, TUMOR; DRUG DISCOVERY; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MORPHOLINES; PROTEIN-SERINE-THREONINE KINASES; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; TROPANES;

EID: 72049122106     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.10.075     Document Type: Article

References (15)

1. Verheijen J.C., Yu K., and Zask A. Ann. Rep. Med. Chem. 43 (2008) 189
2. Verheijen J.C., and Zask A. Drugs Future 32 (2007) 537
3. Folkes A.J., Ahmadi K., Alderton W.K., Alix S., Baker S.J., Box G., Chuckowree I.S., Clarke P.A., Depledge P., Eccles S.A., Friedman L.S., Hayes A., Hancox T.C., Kugendradas A., Lensun L., Moore P., Olivero A.G., Pang J., Patel S., Pergl-Wilson G.H., Raynaud F.I., Robson A., Saghir N., Salphati L., Sohal S., Ultsch M.H., Valenti M., Wallweber H.J.A., Wan N.C., Wiesmann C., Workman P., Zhyvoloup A., Zvelebil M.J., and Shuttleworth S.J. J. Med. Chem. 51 (2008) 5522
4. Hayakawa M., Kaizawa H., Moritomo H., Koizumi T., Ohishi T., Okada M., Ohta M., Tsukamoto S.i., Parker P., Workman P., and Waterfield M. Bioorg. Med. Chem. 14 (2006) 6847
5. Olivero, A. G.; Heffron, T.; Berry, L.; Berry, M.; Castanedo, G.; Chang, C.; Dotson, J.; Friedman, L. S.; Goldsmith, R.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Pang, J.; Peterson, D.; Prior, W.W.; Salphati, L.; Sampath, D.; Sutherlin, D.; Tsui, V.; Ultsch, M.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y.; Chuckowree, I.; Folkes, A.; Shuttleworth, S. In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009, Abstract nr 2707.
6. Heffron, T. P.; Berry, M.; Castanedo, G.; Chang, C.; Chuckowree, I.; Dotson, J.; Folkes, A.; Gunzner, J.; Lesnick, J.; Lewis, C.; Malesky, K.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Peterson, D.; Salphatis, L.; Sampath, D.; Sutherlin, D.; Tsui, V.; Ultsch, M.; Wan, N. C.; Wang, S.; Wiesman, C.; Wong, S.; Zhu, B.-Y. Poster presented at the 237th ACS National Meeting and Exposition March 22-26, 2009 in Salt Lake City, UT.
7. Zask A., Verheijen J.C., Kaplan J., Curran K., Richard D., Brooijmans N., Lucas J., Toral-Barza L., Zhang W.-G., Hollander I., Gibbons J., Abraham R., Ayral-Kaloustian S., Mansour T., and Yu K. J. Med. Chem. 52 (2009) 5013
8. Nowak, P.; Ayral-Kaloustian, S.; Brooijmans, N.; Cole, D. C.; Curran, K. J.; Ellingboe, J.; Gibbons, J. J.; Hu, B.; Hollander, I.; Kaplan, J.; Malwitz, D. J.; Mansour, T. S.; Toral-Barza, L.; Verheijen, J.; Zask, A.; Zhang, W.-G.; Yu, K. J. Med. Chem., in press. doi:10.1021/jm9012642.
9. Yu Y., 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
10. 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.; Zask, A. J. Med. Chem., in press, doi:10.1021/jm9013828.
11. Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.; Bennett, E.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Mansour, T.; Yu, K. J. Med. Chem., in press, doi:10.1021/jm901415x.
12. Biological test methods have been described before. See:. Toral-Barza L., Zhang W.G., Lamison C., Larocque J., Gibbons J., and Yu K. Biochem. Biophys. Res. Commun. 332 (2005) 304
13. Yu K., Toral-Barza L., Discafani C., Zhang W.G., Skotnicki J., Frost P., and Gibbons J. Endocr.-Relat. Cancer 8 (2001) 249
14. 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
15. 1H NMR, HPLC and MS analysis.