Bis(morpholino-l,3,5-triazine) derivatives: Potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor

Journal of Medicinal Chemistry

Volumn 53, Issue 6, 2010, Pages 2636-2645

  Venkatesan, Aranapakam M ^a   Dehnhardt, Christoph M ^a   Delos Santos, Efren D ^a   Chen, Zecheng ^a   Dos Santos, Osvald D ^a   Ayral Kaloustian, Semiramis ^a   Khafizova, Gulnaz ^a   Brooijmans, Natasja ^a   Mallon, Robert ^a   Hollander, Irwin ^a   Feldberg, Larry ^a   Lucas, Judy ^a   Yu, Ker ^a   Gibbons, James ^a   Abraham, Robert T ^a   Chaudhary, Inder ^a   Mansour, Tarek S ^a  

^a WYETH RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 CHLOROPHENYL) 3 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL]UREA; 1 [4 (1,4' BIPIPERIDINE 1' CARBONYL)PHENYL] 3 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2 YL)PHENYL]UREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 (4 FLUOROPHENYL)UREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 (4 METHYLPHENYL)UREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 [4 (1 HYDROXYETHYL)PHENYL]UREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 [4 (HYDROXYMETHYL)PHENYL]UREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 ETHYLUREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 PHENYLUREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 PYRIDAZIN 4 YLUREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 PYRIDIN 3 YLUREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 3 THIOPHEN 2 YLUREA; 1 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL] 4 PYRIDIN 4 YLUREA; 1 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2 YL)PHENYL] 3 [4 [(4 METHYLPIPERAZINE 1 YL)CARBONYL]PHENYL]UREA; 1 [4 [[4 (DIMETHYLAMINO)PIPERIDIN 1 YL]CARBONYL]PHENYL] 3 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL]UREA; 2,4 DIFLUOROPHENYL 3 [4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL]UREA; 4 [3 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2 YL)PHENYL]UREIDO] N METHYLBENZAMIDE; 4 [3 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2YL)PHENYL]UREIDO]BENZOIC ACID; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METHYL 4 [3 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2 YL)PHENYL]UREIDO]BENZOATE; N [2 (DIMETHYLAMINO)ETHYL] 4 [3 [4 (4,6 DIMORPHOLINO 1,3,5 TRIAZIN 2 YL)PHENYL]UREIDO] N METHYLBENZAMIDE; N [2 (DIMETHYLAMINO)ETHYL] 4 [[[4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL]CARBAMOYL]AMINOBENZAMIDE; N [2 (DIMETHYLAMINO)ETHYL] 4 [[[4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL]PHENYL]CARBAMOYL]AMINOBENZAMIDE; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PKI 587; UNCLASSIFIED DRUG; 1 (4 ((4 (DIMETHYLAMINO)PIPERIDIN 1 YL)CARBONYL)PHENYL) 3 (4 (4,6 DIMORPHOLIN 4 YL 1,3,5 TRIAZIN 2 YL)PHENYL)UREA; 1-(4-((4-(DIMETHYLAMINO)PIPERIDIN-1-YL)CARBONYL)PHENYL)-3-(4-(4,6-DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL)UREA; ADENOSINE TRIPHOSPHATE; MAMMALIAN TARGET OF RAPAMYCIN; MORPHOLINE DERIVATIVE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE; SIGNAL PEPTIDE; TRIAZINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG SYNTHESIS; FEMALE; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; ANIMAL; BINDING COMPETITION; CELL SURVIVAL; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; DRUG SCREENING; GENETICS; HUMAN; METABOLISM; MUTATION; NEOPLASM; NUDE MOUSE; PATHOLOGY; PROTEIN BINDING; PROTEIN TERTIARY STRUCTURE; SURVIVAL; TUMOR CELL LINE;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ADENOSINE TRIPHOSPHATE; ANIMALS; AREA UNDER CURVE; BINDING, COMPETITIVE; CELL LINE, TUMOR; CELL SURVIVAL; FEMALE; HUMANS; INHIBITORY CONCENTRATION 50; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; MICE, NUDE; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MORPHOLINES; MUTATION; NEOPLASMS; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTEIN-SERINE-THREONINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; SURVIVAL ANALYSIS; TRIAZINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77949785193     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901830p     Document Type: Article

References (32)

1. (a) Vivanco, I.; Sawyers, C. L. The phosphatidylinositol-3-kinase Akt pathway in human cancer. Nat. Rev. Cancer 2002, 2,489-501.
2. (b) Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. 2009, 8, 627-644.
3. (c) Lempiainen, H.; Halazonetis, T. D. Emerging common themes in regulation of PIKKS and PI3Ks. EMBO J. 2009,28,3067-3073.
4. Yap, T. A.; Garrett, M. D.; Walton, M. I.; Raynand, F.; deBono, J. S.; Workman, P. Targeting the PI3K-Akt-mTor pathway, progress, pitfalls and promises. Curr. Opin. Pharmacol. 2008, 8, 393-414.
5. Bellacosa, A.; Kumar, C. C.; Dicristofano, A.; Testa, J. R. Activation of Akt kinases in cancer: implications for therapeutic targetting. Adv. Cancer Res. 2005, 94, 29-86.
6. Manning, B. D.; Cantley, L. C. Akt/PKB signaling: navigating down stream. Cell 2007, 129,1261-1274.
7. Engelman, J. A.; Luo, J.; Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 2006, 7, 606-619.
8. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B. Exploiting the PI3K/Akt pathway for cancer drug discovery. Nat. Rev. Drug Discovery 2005, 4, 988-1004.
9. Maehama, T.; Dixon, J. E. The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-triphosphate. J. Biol. Chem. 1998, 273, 13375-13378.
10. Ali, I. U.; Schriml, L. M.; Dean, M. Mutational spectra of PTEN/ MMACI gene: a tumor suppressor with lipid phosphatase activity. J. Natl. Cancer Inst. 1999, 91, 1922-1932.
11. Shayesteh, L.; Kuo, W.; Baldocchi, R.; Godfrey, T.; Collins, C.; Pinkel, D.; Powell, B.; Mills, G. B.; Gray, J. W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 1999, 21, 99-102.
12. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Wilson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency mutations of the PIK3CA gene in human cancers. Science 2004, 30, 554.
13. Parsons, D. W.; Wang, T. L.; Samuels, Y.; Bardelli, A.; Cummins, J. M.; De Long, L.; Silliman, N.; Ptak, J.; Szabo, S.; Wilson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Lengauer, C.; Velculescu, V. E. Colorectal cancer: mutations in a signaling pathway. Nature 2005, 436, 792.
14. Vogt, P. K.; Bader, A. G.; Kang, S. PI3-kinase hidden potential revealed. Cell Cycle 2006, 5, 946-949.
15. Workman, P.; Clarke, P. A.; Guillard, S.; Raynaud, F. 1. Drugging the PI3 kinome. Nat. Biotechnol. 2006, 24, 794-796.
16. Fan, Q. W.; Knight, Z. A.; Goldenberg, D. D.; Yu, W.; Mostov, K. E.; Stokoe, D.; Shokat, K. M.; Weiss, W. A. A dual PI3 kinase/ mTor inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006, 9, 341-349.
17. Vlahos, C J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A specific inhibitor of phosphatidylinositol-3-kinase, 2-(4-morpholinyl)-8phenyl-4H-1- benzopyran-4-one(LY294002). J. Biol. Chem. 1994, 269, 5241-5248.
18. Yaguchi, S.; Fukui, Y.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.; Gouda, H.; Hirono, S.; Yamazaki, K.; Yamori, T. Antitumor activity of ZSTK474, a new phosphatidylinositol-3-kinase inhibitor. J. Natl. Cancer Inst. 2006, 98, 545-556.
19. Kong, D.; Yamori, T. ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol-3-kinase isoform. Cancer Sci. 2007,98, 1638-1642.
20. Folkes, A. J.; Ahmadi, K.; Alderto, 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.; Weismann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1Hindazol-4-yl)-6-(4-methane sulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bio-available inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 2008, 51, 5522-5532.
21. (a) Stauffer, F.; Maira, S. M.; Furet, P.; Garcia-Echeverria, C Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. Bioorg. Med. Chem. Lett. 2008, 18, 1027-1030.
22. (b) Maira, S. M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 2008, 7, 1851-1863.
23. Garlich, J. R.; De, P.; Dey, N.; Su, J. D.; Peng, X.; Miller, A.; Murali, R.; Lu, Y.; Mills, G. B.; Kundra, V.; Shu, H.-K.; Peng, Q.; Durden, D. L. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008, 68, 206-215.
24. (a) 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.; Yu, K. ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. J. Med. Chem. 2009, 52, 5013-5016.
25. (b) Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu., K. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors. J. Med. Chem. 2009, 52, 7942-7945.
26. (c) Dehnhardt, C. M.; Venkatesan, A. M.; Chen, Z.; Delos Santos, E.; Dos Santos, O.; Bursavich, M.; Gilbert, A. M.; Ellingboe, J. W.; Ayral-Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Chaudhary, I.; Yu, K.; Gibbons, J.; Abraham, R.; Mansour, T. S. Lead optimization of N3 substituted-7-morpholino-triazolopyrimidines as dual phosphoinositide 3-kinase and mammalian target of rapamycin inhibitors: discovery of PKI-402. J. Med. Chem. 2010, 53, 798-810.
27. Yang, X.; Li, P.; Feldberg, L.; Kim, S. C.; Bowman, M.; Hollander, I.; Mallon, R.; Wolf, S. F. A directly labelled TR-FRET assay for monitoring phosphoinositide-3-kinase activity. Comb. Chem. High Throughput Screening 2006, 9, 565-570.
28. Toral-Barza, L.; Zhang, W. G.; Lamison, C.; Larocque, J.; Gibbons, J.; Yu, K. Biochem. Biophys. Res. Commun. 2005, 332, 304-310.
29. Yu, K.; Toral-Barza, L.; Discafani, C.; Zhang,W. G.; Skotnicki, J.; Frost, P.; Gibbons, J. Endocr-Relat. Cancer 2001, 8, 249-258.
30. Venkatesan, A. M.; Dehnhardt, C. M.; Chen, Z.; Delos Santos, E.; Dos Santos, O; Bursavich, M.; Gilbert, A. M.; Ellingboe, J. W.; Ayral-Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Yu, K.; Gibbons, J.; Abraham, R.; Mansour, T. S. Novel Imidazolopyrimidines as dual PI3-kinase, mTOR inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 653-657.
31. Chen, Z.; Venkatesan, A. M.; Dehnhardt, C. M.; Ayral-Kaloustian, S.; Mansour, T. S.; Brooijmans, N.; Mallon, R.; Hollander, I.; Yu, K. Discovery of Novel Pyrrolo[3,2-d]pyrimidine Derivatives as PI#Kinase Inhibitors. Presented at the 238th National Meeting of the American Chemical Society, Washington, D.C., August 16-20, 2009.
32. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958, 53,457-481.