Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 17, 2012, Pages 5714-5720

  Wurz, Ryan P ^a   Liu, Longbin ^a   Yang, Kevin ^a   Nishimura, Nobuko ^a   Bo, Yunxin ^a   Pettus, Liping H ^a   Caenepeel, Sean ^a   Freeman, Daniel J ^a   McCarter, John D ^a   Mullady, Erin L ^a   Miguel, Tisha San ^a   Wang, Ling ^a   Zhang, Nancy ^a   Andrews, Kristin L ^a   Whittington, Douglas A ^a   Jiang, Jian ^a   Subramanian, Raju ^a   Hughes, Paul E ^a   Norman, Mark H ^a  

^a AMGEN INC   (United States)

Author keywords

Mammalian target of rapamycin; mTOR; Oncology; Phosphoinositide 3 kinase; PI3K; Sulfonamide; Triazine

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MOLECULAR SCAFFOLD; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; SULFONAMIDE; TRIAZINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL ASSAY; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME ASSAY; ENZYME PHOSPHORYLATION; FEMALE; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; FEMALE; HUMANS; MICE; MOLECULAR DOCKING SIMULATION; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RATS; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TOR SERINE-THREONINE KINASES; TRIAZINES;

MAMMALIA; RATTUS;

EID: 84865115694     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.06.078     Document Type: Article

References (33)

1. T. Crabbe, M.J. Welham, and S.G. Ward Trends Biochem. Sci. 32 2007 450
2. M.P. Wymann, M. Zvelebil, and M. Laffargue Trends Pharmacol. Sci. 24 2003 366
3. I. Vivanco, and C.L. Sawyers Nat. Rev. Cancer 2 2002 489
4. P. Liu, H. Cheng, T.M. Roberts, and J.J. Zhao Nat. Rev. Drug. Disc. 8 2009 627
5. T.A. Yap, M.D. Garrett, M.I. Walton, F. Raynaud, J.S. de Bono, and P. Workman Curr. Opin. Pharm. 8 2008 393
6. N.T. Ihle, and G. Powis Mol. Cancer Ther. 8 2009 1
7. R. Marone, V. Cmiljanovic, B. Giese, and M.P. Wymann Biochim. Biophys. Acta 1784 2008 159
8. For selected recent examples of selective PI3K inhibitors see: T.P. Heffron, B. Wei, A. Olivero, S.T. Staben, V. Tsui, S. Do, J. Dotson, A.J. Folkes, P. Goldsmith, R. Goldsmith, J. Gunzner, J. Lesnick, C. Lewis, S. Mathieu, J. Nonomiya, S. Shuttleworth, D.P. Sutherlin, N.C. Wan, S. Wang, C. Wiesmann, and D.-Y. Zhu J. Med. Chem. 54 2011 7815
9. A.J. Folkes, K. Ahmadi, W.K. Alderton, S. Alix, S.J. Baker, G. Box, I.S. Chuckowree, P.A. Clarke, P. Depledge, S.A. Eccles, L.S. Friedman, A. Hayes, T.C. Hancox, A. Kugendradas, L. Lensun, P. Moore, A.G. Olivero, J. Pang, S. Patel, G.H. Pergl-Wilson, F.I. Raynaud, A. Robson, N. Saghir, L. Salphati, S. Sohal, M.H. Ultsch, M. Valenti, H.J.A. Wallweber, N.C. Wan, C. Wiesmann, P. Workman, A. Zhyvoloup, M.J. Zvelebil, and S.J. Shuttleworth J. Med. Chem. 51 2008 5522
10. Z.A. Knight, G.G. Chiang, P.J. Alaimo, D.M. Kenski, C.B. Ho, K. Coan, R.T. Abraham, and K.M. Shokat Bioorg. Med. Chem. 12 2004 4749
11. For selected recent examples of dual PI3K/mTOR inhibitors see: D.P. Sutherlin, L. Bao, M. Berry, G. Castanedo, I. Chuckowree, J. Dotson, A. Folks, L. Friedman, R. Goldsmith, J. Gunzner, T. Heffron, J. Lesnick, C. Lewis, S. Mathieu, J. Murray, J. Nonomiya, J. Pang, N. Pegg, W.W. Prior, L. Rouge, L. Salphati, D. Sampath, Q. Tian, V. Tsui, N.C. Wan, S. Wang, B. Wei, C. Wiesmann, P. Wu, B.-Y. Zhu, and A. Olivero J. Med. Chem. 54 2011 7579
12. D.P. Sutherlin, D. Sampath, M. Berry, G. Castanedo, Z. Chang, I. Chuckowree, J. Dotson, A. Folkes, L. Friedman, R. Goldsmith, T. Heffron, L. Lee, J. Lesnick, C. Lewis, S. Mathieu, J. Nonomiya, A. Olivero, J. Pang, W.W. Prior, L. Salphati, S. Sideris, Q. Tian, V. Tsui, N.C. Wan, S. Wang, C. Wiesmann, S. Wong, and B.-Y. Zhu J. Med. Chem. 53 2010 1086
13. S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chne, A. De Pover, K. Schoemaker, D. Fabbro, D. Gabriel, M. Simonen, L. Murphy, P. Finan, W. Sellers, and C. García-Echeverría Mol. Cancer Ther. 7 2008 1851
14. D. Holmes Nat. Rev. Drug Disc. 10 2011 563
15. K.D. Courtney, R.B. Corcoran, and J.A. Engelman J. Clin. Oncol. 28 2010 1075
16. N.D. D'Angelo, T.-S. Kim, K. Andrews, S.K. Booker, S. Caenepeel, K. Chen, D. Freeman, J. Jiang, J.D. McCarter, T. San Miguel, E.L. Mullady, M. Schrag, R. Subramanian, J. Tang, R.C. Wahl, L. Wang, D.A. Whittington, T. Wu, N. Xi, Y. Xu, P. Yakowec, L.P. Zalameda, N. Zhang, P. Hughes, and M.H. Norman J. Med. Chem. 54 2011 1789
17. Additional efforts towards this goal resulted in the exploration of an imidazolopyridazine scaffold, see: M.M. Stec, K.L. Andrews, S.K. Booker, S. Caenepeel, D.J. Freeman, J. Jiang, H. Liao, J. McCarter, E.L. Mullady, T. San Miguel, R. Subramanian, N. Tamayo, L. Wang, K. Yang, L.P. Zalameda, N. Zhang, P.E. Hughes, and M.H. Norman J. Med. Chem. 54 2011 5174
18. Quinoline/quinoxaline scaffolds were also evaluated, see: N. Nishimura, A. Siegmund, L. Liu, K. Yang, M.C. Bryan, K.L. Andrews, Y. Bo, S.K. Booker, S. Caenepeel, D. Freeman, H. Liao, J. McCarter, E.L. Mullady, T. San Miguel, R. Subramanian, N. Tamayo, L. Wang, D.A. Whittington, L. Zalameda, N. Zhang, P.E. Hughes, and M.H. Norman J. Med. Chem. 54 2011 4735
19. The initial formulation was: 20% captisol, 2% HPMC, 1% Tween 80.
20. The formulation was the same as ref. 13 except dissolve compound 1 at pH 9.0 then readjust pH to 7.0.
21. A.L. Smith, N.D. D'Angelo, Y.Y. Bo, S.K. Booker, V.J. Cee, B. Herberich, F.-T. Hong, C.L.M. Jackson, B.A. Lanman, L. Liu, N. Nishimura, L.H. Pettus, A.B. Reed, S. Tadesse, N.A. Tamayo, R.P. Wurz, K. Yang, K.L. Andrews, D.A. Whittington, J.D. McCarter, T. San Miguel, L. Zalameda, J. Jiang, R. Subramanian, E.L. Mullady, S. Caenepeel, D.J. Freeman, L. Wang, N. Zhang, T. Wu, P.E. Hughes, and M.H. Norman J. Med. Chem. 55 2012 5188
22. PI3Kγ is used as the more amenable surrogate protein whose structure is highly homologous to PI3Kα. Residue numbers in the text refers to the PI3Kγ isoform. The X-ray crystal structure of PI3Kα has been reported, see: C.-H. Huang, D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V.E. Velculescu, K.W. Kinzler, B. Vogelstein, S.B. Gabelli, and L.M. Amzel Science 318 2007 1744
23. A structurally related linker binder moiety has been reported in PF-04691502, see: H. Cheng, S. Bagrodia, S. Bailey, M. Edwards, J. Hoffman, Q. Hu, R. Kania, D.R. Knighton, M.A. Marx, S. Ninkovic, S. Sun, and E. Zhang Med. Chem. Commun. 1 2010 139
24. See also: K.K.C. Liu, X. Huang, S. Bagrodia, J.H. Chen, S. Greasley, H. Cheng, S. Sun, D. Knighton, C. Rodgers, K. Rafidi, A. Zou, J. Xiao, and S. Yan Bioorg. Med. Chem. Lett. 21 2011 1270
25. S. Bhagwanth, G.M. Adjabeng, and K.R. Hornberger Tetrahedron Lett. 50 2009 1582
26. A.S. Guram, A.O. King, J.G. Allen, X. Wang, L.B. Schenkel, J. Chan, E.E. Bunel, M.M. Faul, R.D. Larsen, M.J. Martinelli, and P.J. Reider Org. Lett. 8 2006 1787
27. A.S. Guram, X. Wang, E.E. Bunel, M.M. Faul, R.D. Larsen, and M.J. Martinelli J. Org. Chem. 72 2007 5104
28. For detailed experimental procedures see: Andrews, K.; Bo, Y. Y.; Booker, S.; Cee, V. J.; D'Angelo, N.; Herberich, B. J.; Hong, F.-T.; Jackson, C. L. M.; Lanman, B. A.; Liao, H.; Liu, L.; Nishimura, N.; Norman, M. H.; Pettus, L. H.; Reed, A. B.; Smith, A. L.; Tadesse, S.; Tamayo, N. A.; Wu, B.; Wurz, R.; Yang, K. WO 2010126895, November 4, 2010.
29. Physicochemical properties were calculated using the Daylight Toolkit, within Amgen's proprietary software (ADAPT). For more information see: (a) Daylight Chemical Information Systems Inc. http://www.daylight.com.
30. S.J. Cho, Y. Sun, and W.J. Harte Comput.-Aided Mol. Des. 20 2006 249
31. It should be noted that the inhibition of phosphorylation of Akt (pAkt) at S473 of PTEN-null cell lines, such as U87 MG, are also sensitive to mTOR inhibition, therefore the cell IC50 values can be a composite of the various PI3K isoforms as well as mTOR, see: M.S. Neshat, I.K. Mellinghoff, C. Tran, B. Stiles, G. Thomas, R. Petersen, P. Frost, J.J. Gibbons, H. Wu, and C.L. Sawyers Proc. Natl. Acad. Sci. U.S.A. 98 2001 10314
32. S.D. Knight, N.D. Adams, J.L. Burgess, A.M. Chaudhari, M.G. Darcy, C.A. Donatelli, J.I. Luengo, K.A. Newlander, C.A. Parrish, L.H. Ridgers, M.A. Sarpong, S.J. Schmidt, G.S. Van Aller, J.D. Carson, M.A. Diamond, P.A. Elkins, C.M. Gardiner, E. Garver, S.A. Gilbert, R.R. Gontarek, J.R. Jackson, K.L. Kershner, L. Luo, K. Raha, C.S. Sherk, C.-M. Sung, D. Sutton, P.J. Tummino, R.J. Wegrzyn, K.R. Auger, and D. Dhanak ACS Med. Chem. Lett. 1 2010 39
33. J.M. Backer Biochem. J. 410 2008 1