ATP-competitive inhibitors of mTOR: An update

Current Medicinal Chemistry

Volumn 18, Issue 20, 2011, Pages 2995-3014

  Schenone, S ^a   Brullo, C ^a   Musumeci, F ^a   Radi, M ^b   Botta, M ^b  

^a UNIVERSITY OF GENOA   (Italy)

^b UNIVERSITY OF SIENA   (Italy)

Author keywords

ATP competitive; Cancer; Inhibitors; MTOR; Rapamycin; Serine threonine kinase

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 6 (1H INDOL 5 YL) 4 MORPHOLIN 4 YL 1 [1 (PYRIDIN 3 YLMETHYL)PIPERIDIN 4 YL] 1H PYRAZOLO[3,4 D]PYRIMIDINE; AZD 8055; EVEROLIMUS; GNE 477; GSK 2126458; IMATINIB; IMIDAZOPYRAZINE DERIVATIVE; IMIDAZOTRIAZINE DERIVATIVE; INK 128; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OSI 027; OXA 01; PP 242; PP 30; PYRIDOPYRIMIDINE DERIVATIVE; PYRIMIDOISOQUINOLINE DERIVATIVE; PYRROLOPYRIDINE DERIVATIVE; RAPAMYCIN; RIDAFOROLIMUS; SORAFENIB; SUNITINIB; TEMSIROLIMUS; TORIN 1; TOSIREL; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 600; WJD 008; WYE 132; WYE 354; WYE 687;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; CANCER CELL; CELL GROWTH; CELL PROLIFERATION; CHRONIC MYELOID LEUKEMIA; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG STRUCTURE; DRUG WITHDRAWAL; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; GLIOBLASTOMA; GLIOMA; GRAFT REJECTION; HODGKIN DISEASE; HUMAN; IC 50; KAPOSI SARCOMA; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; LEUKEMIA CELL; LIVER CELL CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MANTLE CELL LYMPHOMA; MELANOMA; MOLECULAR MODEL; MUCOSA INFLAMMATION; MULTIPLE MYELOMA; NERVE SHEATH TUMOR; NEUROENDOCRINE TUMOR; NONHUMAN; PHARMACOPHORE; PNEUMONIA; PRIMARY EFFUSION LYMPHOMA; PROSTATE CANCER; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; REVIEW; SARCOMA; SIGNAL TRANSDUCTION; SOLID TUMOR; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DISCOVERY; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; TOR SERINE-THREONINE KINASES;

EID: 79959926021     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986711796391651     Document Type: Review

References (159)

1. Brown, E. J.; Albers, M. W.; Shin, T. B.; Ichikawa, K.; Keith, C. T.; Lane, W. S.; Schreiber, S. L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 1994, 369, 756-758.
2. Chiu, M. I.; Katz, H.; Berlin, V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl. Acad. Sci. U S A, 1994, 91, 12574-12578.
3. Sabatini, D. M.; Erdjument-Bromage, H.; Lui, M.; Tempst, P.; Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycindependent fashion and is homologous to yeast TORs. Cell, 1994, 78, 35-43. (Pubitemid 24228298)
4. Jacinto, E.; Hall, M. N. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell. Biol, 2003, 4, 117-126. (Pubitemid 36172695)
5. Vogh, P. K. PI 3-kinase, mTOR, protein synthesis and cancer. Trends Mol. Med., 2001, 7, 482-484.
6. Carracedo, A.; Pandolfi, P. P. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene, 2008, 27, 5527-5541.
7. Sekulic, A.; Hudson, C. C.; Homme, J. L.; Yin, P.; Otterness, D. M.; Karnitz, L. M.; Abraham, R. T. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res., 2000, 60, 3504-3513. (Pubitemid 30482170)
8. Gingras, A. C.; Raught, B.; Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev., 2001, 15, 807-826. (Pubitemid 32295062)
9. Kim, D. H.; Sarbassov, D. D.; Ali, S. M.; King, J. E.; Latek, R. R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D. M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 2002, 110, 163-175. (Pubitemid 34876545)
10. Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18, 1926-1945. (Pubitemid 39071573)
11. Gibbons, J. J.; Abraham, R. T.; Yu, K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Seminars in Oncology, 2009, 36, S3-S17.
12. Holz, M. K.; Blenis, J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem., 2005, 280, 25489-25493.
13. Gingras, A. C.; Gygi, S. P.; Raught, B.; Polakiewicz, R. D.; Abraham, R. T.; Hoekstra, M. F.; Aebersold, R; Sonenberg, N. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev., 1999, 13, 1422-1437. (Pubitemid 29270247)
14. Ma, X. M.; Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell. Biol., 2009, 10, 307-318.
15. Easton, J. B.; Houghton, P. J. mTOR and cancer therapy. Oncogene, 2006, 25, 6436-6446. (Pubitemid 44582287)
16. Meijer, A. J.; Codogno, P. Signalling and autophagy regulation in health, aging and disease. Mol. Aspects Med., 2006, 27, 411-425. (Pubitemid 44466652)
17. Dowling, R. J.; Topisirovic, I.; Fonseca, B. D.; Sonenberg, N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta, 2010, 1804, 433-439.
18. Sarbassov, D. D.; Ali, S. M.; Kim, D. H.; Guertin, D. A.; Latek, R. R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D. M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol., 2004, 14, 1296-1302. (Pubitemid 38991819)
19. Sarbassov, D. D.; Guertin, D. A.; Ali, S. M.; Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307, 1098-1101. (Pubitemid 40262113)
20. Huang, J.; Dibble, C. C.; Matsuzaki, M.; Manning, B. D. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol., 2008, 28, 4104-4115. (Pubitemid 351812994)
21. Sparks, C. A.; Guertin, D. A. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene, 2010, 29, 3733-3744.
22. Cheng, S. W.; Fryer, L. G.; Carling, D.; Shepherd, P. R. Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J. Biol. Chem., 2004, 279, 15719-15722. (Pubitemid 38509255)
23. Acosta-Jaquez, H. A.; Keller, J. A.; Foster, K. G.; Ekim, B.; Soliman, G. A.; Feener, E. P.; Ballif, B. A.; Fingar, D. C. Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol. Cell. Biol., 2009, 29, 4308-4324.
24. Zhou, H.; Huang, S. The complexes of mammalian target of rapamycin. Curr. Protein Pept. Sci., 2010, 11, 409-424.
25. Carnero, A. The PKB/AKT pathway in cancer. Curr. Pharm. Des., 2010, 16, 34-44.
26. Shor, B.; Gibbons, J. J.; Abraham, R. T.; Yu, K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle, 2009, 8, 3831-3837.
27. Yuan, T. L.; Cantley, L. C. PI3K pathway alterations in cancer: variation on a theme. Oncogene, 2008, 27, 5497-5510.
28. Strimpakos, A. S.; Karapanagiotou, E. M.; Saif, M. W.; Syrigos, K. N. The role of mTOR in the management of solid tumors: an overview. Cancer Treat. Rev., 2009, 35, 148-159.
29. Memmott, R. M.; Dennis, P. A. Akt-dependent and-independent mechanisms of mTOR regulation in cancer. Cell Signal., 2009, 21, 656-664.
30. Sabatini, D. M. mTOR and cancer: insights into a complex relationship, Nat. Rev. Cancer, 2006, 6, 729-734. (Pubitemid 44286004)
31. Efeyan, A.; Sabatini, D. M. mTOR and cancer: many loops in one pathway. Curr. Opin. Cell. Biol., 2010, 22, 169-176.
32. Klatte, T.; Pantuck, A. J. Molecular biology of renal cortical tumors. Urol. Clin. N. Am., 2008, 35, 573-580.
33. Yuan, R.; Kay, A.; Berg, W. J.; Lebwohl, D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J. Hematol. Oncol., 2009, 2, 45.
34. Markova, B.; Albers, C.; Breitenbuecher, F.; Melo, J. V.; Brümmendorf, T. H.; Heidel, F.; Lipka, D.; Duyster, J.; Huber, C.; Fischer, T. Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway. Oncogene, 2010, 29, 739-751.
35. Carayol, N.; Vakana, E.; Sassano, A.; Kaur, S.; Goussetis, D. J.; Glaser, H.; Druker, B. J.; Donato, N. J.; Altman, J. K.; Barr, S.; Platanias, L. C. Critical roles for mTORC2-and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl. Acad. Sci. USA, 2010, 107, 12469-12474.
36. Sudarsanam, S.; Johnson, D. E. Functional consequences of mTOR inhibition. Curr. Opin. Drug Discov. Dev. 2010, 13, 31-40.
37. Ciuffreda, L.; Di Sanza, C.; Incani, U. C.; Milella, M. The mTOR pathway: a new target in cancer therapy. Curr. Cancer Drug Tar., 2010, 10, 484-495.
38. Dowling, R. J.; Pollak, M.; Sonenberg, N. Current status and challenges associated with targeting mTOR for cancer therapy. BioDrugs, 2009, 23, 77-91.
39. Liu, Q.; Thoreen, C.; Wang, J.; Sabatini, D.; Gray, N. S. mTOR Mediated anti-cancer drug discovery. Drug Discov. Today Ther. Strateg., 2009, 6, 47-55.
40. Bhagwat, S. V.; Crew, A. P. Novel inhibitors of mTORC1 and mTORC2. Curr. Opin. Investig. Drugs, 2010, 11, 638-645.
41. Richard, D. J.; Verheijen, J. C.; Zask, A. Recent advances in the development of selective, ATP-competitive inhibitors of mTOR. Curr Opin. Drug Discov. Dev., 2010, 13, 428-440.
42. Albert, S.; Serova, M.; Dreyer, C.; Sablin, M. P.; Faivre, S.; Raymond, E. New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Exp. Opin. Investig. Drugs, 2010, 19, 919-930.
43. Garcia-Echeverria, C. Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. Bioorg. Med. Chem. Lett., 2010, 20, 4308-4312.
44. Easton, J. B.; Houghton, P. J. mTOR and cancer therapy. Oncogene, 2006, 25, 6436-6446. (Pubitemid 44582287)
45. Strimpakos, A. S.; Karapanagiotou, E. M.; Saif, M. W.; Syrigos, K. N. The role of mTOR in the management of solid tumors: an overview. Cancer Treat. Rev., 2009, 35, 148-159.
46. Teachey, D. T.; Grupp, S. A.; Brown, V. I. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br. J. Haematol., 2009, 145, 569-580.
47. Campistol, J. M.; Eris, J.; Oberbauer, R.; Friend, P.; Hutchison, B.; Morales, J. M.; Claesson, K.; Stallone, G.; Russ, G.; Rostaing, L.; Kreis, H.; Burke, J. T.; Brault, Y.; Scarola, J. A.; Neylan, J. F. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J. Am. Soc. Nephrol., 2006, 17, 581-589.
48. Stallone, G.; Schena, A.; Infante, B.; Di Paolo, S.; Loverre, A., Maggio, G.; Ranieri, E.; Gesualdo, L.; Schena, F. P.; Grandaliano, G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N. Engl. J. Med., 2005, 352, 1317-1323. (Pubitemid 40411498)
49. Kwitkowski, V. E.; Prowell, T. M.; Ibrahim, A.; Farrell, A. T.; Justice, R.; Mitchell, S. S.; Sridhara, R.; Pazdur, R. FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. Oncologist, 2010, 15, 428-435.
50. Chan, S.; Scheulen, M. E.; Johnston, S.; Mross, K.; Cardoso, F.; Dittrich, C.; Eiermann, W.; Hess, D.; Morant, R.; Semiglazov, V.; Borner, M.; Salzberg, M.; Ostapenko, V.; Illiger, H. J.; Behringer, D.; Bardy-Bouxin, N.; Boni, J.; Kong, S.; Cincotta, M.; Moore, L. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol., 2005, 23, 5314-5322. (Pubitemid 46206985)
51. Galanis, E.; Buckner, J. C.; Maurer, M. J.; Kreisberg, J. I.; Ballman, K.; Boni, J.; Peralba, J. M.; Jenkins, R. B.; Dakhil, S. R.; Morton, R. F.; Jaeckle, K. A.; Scheithauer, B. W.; Dancey, J.; Hidalgo, M.; Walsh, D. J. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study. J. Clin. Oncol., 2005, 23, 5294-5304. (Pubitemid 46206983)
52. Robins, H. I.; Wen, P. Y.; Chang, S. M.; Kuhn, J.; Lamborn, T.; Cloughesy, T.; Glibert, M. R.; Yung, W. K.; Dancey, J.; Prados, M. D. Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04-02). J. Clin. Oncol., 2007 ASCO Annual Meeting Proceedings 25, 18S.
53. Gadducci, A.; Tana, R.; Cosio, S.; Fanucchi, A.; Genazzani, A. R. Molecular target therapies in endometrial cancer: from the basic research to the clinic. Gynecol. Endocrinol., 2008, 24, 239-249. (Pubitemid 351891652)
54. Margolin, K.; Longmate, J.; Baratta, T.; Synold, T.; Christensen, S.; Weber, J.; Gajewski, T.; Quirt, I.; Doroshow, J. H. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer, 2005, 104, 1045-1048. (Pubitemid 41170233)
55. Dancey, J. E.; Curiel, R.; Purvis, J. Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. Semin. Oncol., 2009, 36, S46-S58.
56. Stock, C.; Zaccagnini, M.; Schulze, M.; Teber, D.; Rassweiler, J. J. Temsirolimus. Recent Results Cancer Res., 2010, 184, 189-197.
57. Del Bufalo, D.; Ciuffreda, L.; Trisciuoglio, D.; Desideri, M.; Cognetti, F.; Zupi, G.; Milella, M. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res., 2006, 66, 5549-5554. (Pubitemid 43927103)
58. O'Reilly, T.; McSheehy, P. M. Biomarker development for the clinical activity of the mTOR inhibitor Everolimus (RAD001): processes, limitations, and further proposals. Transl. Oncol., 2010, 3, 65-79.
59. Houghton, P. J. Everolimus. Clin. Cancer Res., 2010, 16, 1368-1372.
60. Yee, K. W.; Zeng, Z.; Konopleva, M.; Verstovsek, S.; Ravandi, F.; Ferrajoli, A.; Thomas, D.; Wierda, W.; Apostolidou, E.; Albitar, M.; O'Brien, S.; Andreeff, M.; Giles, F. J. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res., 2006, 12, 5165-5173. (Pubitemid 44453345)
61. Mancini, M.; Petta, S.; Martinelli, G.; Barbieri, E.; Santucci, M. A. RAD 001 (everolimus) prevents mTOR and Akt late re-activation in response to imatinib in chronic myeloid leukemia. J. Cell. Biochem., 2010, 109, 320-328.
62. Mancini, M.; Corradi, V.; Petta, S.; Martinelli, G.; Barbieri, E.; Santucci, M. A. mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. Leuk. Res., 2010, 34, 641-648.
63. Wang, Z. G.; Fukazawa, T.; Nishikawa, T.; Watanabe, N.; Sakurama, K.; Motoki, T.; Hatakeyama, S.; Omori, O.; Ohara, T.; Tanabe, S.; Fujiwara, Y.; Takaoka, M.; Shirakawa, Y.; Yamatsuji, T.; Tanaka, N.; Naomoto, Y. RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. Oncol. Rep., 2010, 23, 1167-1172.
64. Zatelli, M. C.; Minoia, M.; Martini, C.; Tagliati, F.; Ambrosio, M. R.; Schiavon, M.; Buratto, M.; Calabrese, F.; Gentilin, E.; Cavallesco, G.; Berdonini, L.; Rea, F.; Degli Uberti, E. C. Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. Endocr. Relat. Cancer, 2010, 17, 719-729.
65. Mahalingam, D.; Sankhala, K.; Mita, A.; Giles, F. J.; Mita, M. M. Targeting the mTOR pathway using deforolimus in cancer therapy. Future Oncol., 2009, 5, 291-303.
66. Mita, M.; Sankhala, K.; Abdel-Karim, I.; Mita, A.; Giles, F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Exp. Opin. Investig. Drugs, 2008, 17, 1947-1954.
67. Mita, M. M.; Mita, A. C.; Chu, Q. S.; Rowinsky, E. K.; Fetterly, G. J.; Goldston, M.; Patnaik, A.; Mathews, L.; Ricart, A. D.; Mays, T.; Knowles, H.; Rivera, V. M.; Kreisberg, J.; Bedrosian, C. L.; Tolcher, A. W. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J. Clin. Oncol., 2008, 26, 361-367. (Pubitemid 351171685)
68. Rizzieri, D. A.; Feldman, E.; Dipersio, J. F.; Gabrail, N.; Stock, W.; Strair, R.; Rivera, V. M.; Albitar, M.; Bedrosian, C. L.; Giles, F. J. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res., 2008, 14, 2756-2762.
69. Sankhala, K.; Mita, A.; Kelly, K.; Mahalingam, D.; Giles, F.; Mita, M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol., 2009, 4, 135-142.
70. Figlin, R. A. Mechanisms of disease: survival benefit of temsirolimus validates a role for mTOR in the management of advanced RCC. Nat. Clin. Pract. Oncol., 2008, 5, 601-609.
71. Lane, H. A.; Wood, J. M.; McSheehy, P. M.; Allegrini, P. R.; Boulay, A.; Brueggen, J.; Littlewood-Evans, A.; Maira, S. M.; Martiny-Baron, G.; Schnell, C. R.; Sini, P.; O'Reilly, T. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin. Cancer Res., 2009, 15, 1612-1622.
72. Choi, J.; Chen, J.; Schreiber, S. L.; Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science, 1996, 273, 239-242. (Pubitemid 26285890)
73. Huang, S.; Bjornsti, M. A.; Houghton, P. J. Rapamycins: mechanism of action and cellular resistance. Cancer Biol. Ther., 2003, 2, 222-232.
74. Huang, S.; Houghton, P. J. Targeting mTOR signaling for cancer therapy. Curr. Opin. Pharmacol., 2003, 3, 371-377. (Pubitemid 36908940)
75. Oshiro, N.; Yoshino, K.; Hidayat, S.; Tokunaga, C.; Hara, K.; Eguchi, S.; Avruch, J.; Yonezawa, K. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells, 2004, 9, 359-366. (Pubitemid 38514871)
76. Shor, B.; Zhang, W. G.; Toral-Barza, L.; Lucas, J.; Abraham R. T.; Gibbons, J. J.; Yu, K. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res., 2008, 68, 2934-2943. (Pubitemid 351556294)
77. Sarbassov, D. D.; Ali, S. M.; Sengupta, S.; Sheen, J. H.; Hsu, P. P.; Bagley, A. F.; Markhard, A. L.; Sabatini, D. M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell., 2006, 22, 159-168.
78. Foster, D. A.; Toschi, A. Targeting mTOR with rapamycin: one doses not fit all. Cell Cycle, 2009, 8, 1026-1029.
79. Fang, Y.; Vilella-Bach, M.; Bachmann, R.; Flanigan, A.; Chen. J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science, 2001, 294, 1942-1945. (Pubitemid 33101594)
80. Toschi, A.; Lee, E.; Xu, L.; Garcia, A.; Gadir, N.; Foster, D. A. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol. Cell. Biol., 2009, 29, 1411-1420.
81. Guertin, D. A.; Stevens, D. M.; Saitoh, M.; Kinkel, S.; Crosby, K.; Sheen, J. H.; Mullholland, D. J.; Magnuson, M. A.; Wu, H.; Sabatini, D. M. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell, 2009, 15, 148-159.
82. Nardella, C.; Carracedo, A.; Alimonti, A.; Hobbs, R. M.; Clohessy, J. G.; Chen, Z.; Egia, A.; Fornari, A.; Fiorentino, M.; Loda, M.; Kozma, S. C.; Thomas, G.; Cordon-Cardo, C.; Pandolfi, P. P. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci. Signal., 2009, 2(55):ra2.
83. Apsel, B.; Blair, J. A.; Gonzalez, B.; Nazif, T. M.; Feldman, M. E.; Aizenstein, B.; Hoffman, R.; Williams, R. L.; Shokat, K. M.; Knight, Z. A. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol., 2008, 4, 691-699.
84. Feldman, M. E.; Apsel, B.; Uotila, A.; Loewith, R.; Knight, Z. A.; Ruggero, D.; Shokat, K. M. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol., 2009, 7(2):e38.
85. Janes, M. R.; Limon, J. J.; So, L.; Chen, J.; Lim, R. J.; Chavez, M. A.; Vu, C.; Lilly, M. B.; Mallya, S.; Ong, S. T.; Konopleva, M.; Martin, M. B.; Ren, P.; Liu, Y.; Rommel, C.; Fruman, D. A. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med., 2010, 16, 205-213.
86. 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. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res., 2009, 69, 6232-6240.
87. 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.; Lucas, J.; Hollander, I.; Ayral-Kaloustian, S.; Mansour, T. S.; Yu, K.; Zask, A. Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3, 4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituent. J. Med. Chem., 2009, 52, 8010-8224.
88. 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.
89. Nowak, P.; Cole, D. C.; Brooijmans, N.; Bursavich, M. G.; Curran, K. J.; Ellingboe, J. W.; Gibbons, J. J.; Hollander, I.; Hu, Y.; Kaplan, J.; Malwitz, D. J.; Toral-Barza, L.; Verheijen, J. C.; Zask, A.; Zhang, W. G.; Yu, K. Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase. J. Med. Chem., 2009, 52, 7081-7089.
90. Dumas, J.; Smith, R. A.; Lowinger, T. B. Recent developments in the discovery of protein kinase inhibitors from the urea class. Curr. Opin. Drug Discov. Dev., 2004, 7, 600-616. (Pubitemid 39329863)
91. 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.
92. Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Toral-Barza, L.; Hollander, I.; Lucas, J., Yu, K.; Zask, A. Incorporation of water-solubilizing groups in pyrazolopyrimidine mTOR inhibitors: discovery of highly potent and selective analogs with improved human microsomal stability. Bioorg. Med. Chem. Lett., 2009, 19, 6830-6835.
93. Curran, K. J.; Verheijen, J. C.; Kaplan, J.; Richard, D. J.; Toral-Barza, L., Hollander, I.; Lucas, J.; Ayral-Kaloustian, S.; Yu, K.; Zask, A. Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent. Bioorg. Med. Chem. Lett., 2010, 20, 1440-1444.
94. 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. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res., 2010, 70, 621-631.
95. Kaplan, J.; Verheijen, J. C.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Yu, K.; Zask, A. Discovery of 3, 6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3, 4-d]pyrimidines and 2-arylthieno[3, 2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett., 2010, 20, 640-643.
96. 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.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1H-indazol-4-yl)-6-(4- methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3, 2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem., 2008, 51, 5522-5532.
97. Zask, A.; Verheijen, J. C.; Richard, D. J.; Kaplan, J.; Curran, K.; Toral-Barza, L.; Lucas, J.; Hollander, I.; Yu, K. Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors. Bioorg. Med. Chem. Lett., 2010, 20, 2644-2647.
98. Verheijen, J. C.; Richard, D. J.; Curran, K.; Kaplan, J.; Yu, K.; Zask, A. 2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl) triazines as highly potent and selective ATP competitive mTOR inhibitors: optimization of human microsomal stability. Bioorg. Med. Chem. Lett., 2010, 20, 2648-2653.
99. Tsou, H. R.; MacEwan, G.; Birnberg, G.; Grosu, G.; Bursavich, M. G.; Bard, J.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Mansour, T. S.; Ayral-Kaloustian, S.; Yu, K. Discovery and optimization of 2-(4- substitutedpyrrolo[2, 3-b]pyridin-3-yl) methylene-4-hydroxybenzofuran-3 (2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett., 2010, 20, 2321-2325.
100. Bursavich, M. G.; Brooijmans, N.; Feldberg, L.; Hollander, I.; Kim, S.; Lombardi, S.; Park, K.; Mallon, R.; Gilbert, A. M. Novel benzofuran-3-one indole inhibitors of PI3 kinase-alpha and the mammalian target of rapamycin: hit to lead studies. Bioorg. Med. Chem. Lett., 2010, 20, 2586-2590.
101. Tsou, H. R.; MacEwan, G.; Birnberg, G.; Grosu, G.; Bursavich, M. G.; Bard, J.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Mansour, T. S.; Ayral-Kaloustian, S.; Yu, K. Discovery and optimization of 2-(4- substitutedpyrrolo[2, 3-b]pyridin-3-yl) methylene-4-hydroxybenzofuran-3 (2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett., 2010, 20, 2321-2325.
102. Tsou, H. R.; MacEwan, G.; Birnberg, G.; Zhang, N.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett., 2010, 20, 2259-2263.
103. http://clinicaltrials.gov/.
104. 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. The discovery and optimisation of pyrido[2, 3-d]pyrimidine-2, 4-diamines as potent and selective inhibitors of mTOR kinase. Bioorg. Med. Chem. Lett., 2009, 19, 5950-5953.
105. García-Martínez, J. M.; Moran, J.; Clarke, R. G.; Gray, A.; Cosulich, S. C.; Chresta, C. M.; Alessi, D. R. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem. J., 2009, 421, 29-42.
106. 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. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res., 2010, 70, 288-298.
107. Sini, P.; James, D.; Chresta, C.; Guichard, S. Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy, 2010, 6 (4).
108. Sturgill, T. W.; Hall, M. N. Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha. ACS Chem Biol. 2009, 4, 999-1015.
109. 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. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol Chem., 2009, 284, 8023-8032.
110. Jessen, K.; Wang, S.; Kessler, L.; Guo, X.; Kucharski, J.; Staunton, J.; Lan, L.; Elia, M.; Stewart, J.; Brown, J.; Li, L.; Chan, K.; Martin, M.; Ren, P.; Rommel, C.; Liu, Y. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. Mol. Cancer Ther., 2009, 8(12 Suppl):B148.
111. Miller, N. XL388: A novel, selective, orally bioavailable mTORC1 and mTORC2 inhibitor that demonstrates pharmacodynamic and antitumor activity in multiple human cancer xenograft models. Mol. Cancer Ther., 2009, 8(12 Suppl):B146.
112. Ballou, L. M.; Selinger, E. S.; Choi, J. Y.; Drueckhammer, D. G.; Lin, R. Z. Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl) pyrimido[2, 1-alpha]isoquinolin-4-one. J. Biol. Chem., 2007, 282, 24463-24470. (Pubitemid 47328068)
113. Griffin, R. J.; Fontana, G.; Golding, B. T.; Guiard, S.; Hardcastle, I. R.; Leahy, J. J.; Martin, N.; Richardson, C.; Rigoreau, L.; Stockley, M.; Smith, G. C. Selective benzopyranone and pyrimido[2, 1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro. J. Med. Chem., 2005, 48, 569-585. (Pubitemid 40139799)
114. Ballou, L. M.; Lin, R. Z. Rapamycin and mTOR kinase inhibitors. J. Chem. Biol., 2008, 1, 27-36.
115. Toral-Barza, L.; Zhang, W. G.; Lamison, C.; Larocque, J.; Gibbons, J.; Yu, K. Characterization of the cloned full-length and a truncated human target of rapamycin: activity, specificity, and enzyme inhibition as studied by a high capacity assay. Biochem. Biophys. Res. Commun., 2005, 332, 304-310. (Pubitemid 40719487)
116. Maira, S. M.; Voliva, C.; Garcia-Echeverria, C. Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery. Exp. Opin. Ther. Targets, 2008, 12, 223-238. (Pubitemid 351284964)
117. Maira, S. M.; Finan, P.; Garcia-Echeverria, C. From the bench to the bed side: PI3K pathway inhibitors in clinical development. Curr. Top. Microbiol. Immunol., 2011, 347, 209-239.
118. Brachmann, S.; Fritsch, C.; Maira, S. M.; García- Echeverría, C. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr. Opin. Cell. Biol., 2009, 21, 194-198.
119. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8, 627-644.
120. Maira, S. M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chène, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; García-Echeverría, 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.
121. Serra, V.; Markman, B.; Scaltriti, M.; Eichhorn, P. J.; Valero, V.; Guzman, M.; Botero, M. L.; Llonch, E.; Atzori, F.; Di Cosimo, S.; Maira, M.; Garcia-Echeverria, C.; Parra, J. L.; Arribas, J.; Baselga, J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res., 2008, 68, 8022-8030.
122. Brachmann, S. M.; Hofmann, I.; Schnell, C.; Fritsch, C.; Wee, S.; Lane, H.; Wang, S.; Garcia-Echeverria, C.; Maira, S. M. Specific apoptosis induction by the dual PI3K/mTOR inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc. Nat. Acad. Sci. U. S. A., 2009, 106, 22299-22304.
123. Cao, P.; Maira, S. M.; Garcia-Echeverria, C.; Hedley, D. W. Activity of a novel, dual PI3-kinase/mTOR inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthopic xenografts. Br. J. Cancer, 2009, 100, 1267-1276.
124. Baumann, P.; Mandl-Weber, S.; Oduncu, F.; Schmidmaier, R. The novel orally bioavailable inhibitor of phophoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp. Cell Res., 2009, 315, 485-497.
125. McMillin, D. W.; Ooi, M.; Delmore, J.; Negri, J.; Hayden, P.; Mitsiades, N.; Jakubikova, J.; Maira, S. M.; Garcia-Echeverria, C.; Schlossman, R.; Munshi, N. C.; Richardson, P. G.; Anderson, K. C.; Mitsiades, C. S. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res., 2009, 69, 5835-5842.
126. Bhatt, A. P.; Bhende, P. M.; Sin, S. H.; Roy, D.; Dittmer, D. P.; Damania. B. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood, 2010, 115, 4455-4463.
127. Cho, D. C.; Cohen, M. B.; Panka, D. J.; Collins, M.; Ghebremichael, M.; Atkins, M. B.; Signoretti, S.; Mier, J. W. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin. Cancer Res., 2010, 16, 3628-3638.
128. Liu, T. J.; Koul, D.; LaFortune, T.; Tiao, N.; Shen, R. J.; Maira, S. M.; Garcia-Echevrria, C.; Yung, W. K. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol. Cancer Ther., 2009, 8, 2204-2210.
129. Manara, M. C.; Nicoletti, G.; Zambelli, D.; Ventura, S.; Guerzoni, C.; Landuzzi, L.; Lollini, P. L.; Maira, S. M.; García-Echeverría, C.; Mercuri, M.; Picci, P.; Scotlandi, K. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin. Cancer Res., 2010, 16, 530-540.
130. Marone, R.; Erhart, D.; Mertz, A. C.; Bohnacker, T.; Schnell, C.; Cmiljanovic, V.; Stauffer, F.; Garcia-Echeverria, C.; Giese, B.; Maira, S. M.; Wymann, M. P. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol. Cancer Res., 2009, 7, 601-613.
131. Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.; Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish, C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.; Sung, C.
132. Marone, R.; Cmiljanovic, V.; Giese, B.; Wymann, M. P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta, 2008, 1784, 159-185.
133. Papadopoulos, K. P.; Markman, B.; Tabernero, J.; Patnaik, A.; Heath, E. I.; DeCillis, A.; Laird, D.; Aggarwal, S. K.; Nguyen, L.; LoRusso, P. M. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors. J. Clin. Oncol., 2008, 26, abstr 3510.
134. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.; Ohta, M.; Tsukamoto, S.; Parker, P.; Workman, P.; Waterfield, M. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg. Med. Chem., 2006, 14, 6847-6858. (Pubitemid 44307656)
135. Knight, Z. A.; Gonzalez, B.; Feldman, M. E.; Zunder, E. R.; Goldenberg, D. D.; Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.; Toth, B.; Balla, T.; Weiss, W. A.; Williams, R. L.; Shokat, K. M. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 2006, 125, 733-747.
136. 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. (Pubitemid 43668732)
137. Raynaud, F. I.; Eccles, S.; Clarke, P. A.; Hayes, A.; Nutley, B.; Alix, S.; Henley, A.; Di-Stefano, F.; Ahmad, Z.; Guillard, S.; Bjerke, L. M.; Kelland, L.; Valenti, M.; Patterson, L.; Gowan, S.; de Haven Brandon, A.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Patel, S.; Saghir, N.; Parker, P.; Waterfield, M.; Workman, P. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res., 2007, 67, 5840-5850. (Pubitemid 46985018)
138. Zou, Z. Q.; Zhang, X. H.; Wang, F.; Shen, Q. J.; Xu, J.; Zhang, L. N.; Xing, W. H.; Zhuo, R. J.; Li, D. A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. Int. J. Mol. Med., 2009, 24, 97-101.
139. Zou, C. Y.; Smith, K. D.; Zhu, Q. S.; Liu, J.; McCutcheon, I. E.; Slopis, J. M.; Meric-Bernstam, F.; Peng, Z.; Bornmann, W. G.; Mills, G. B.; Lazar, A. J.; Pollock, R. E.; Lev, D. Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor. Mol. Cancer Ther., 2009, 8, 1157-1168.
140. Chaisuparat, R.; Hu, J.; Jham, B. C.; Knight, Z. A.; Shokat, K. M.; Montaner, S. Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res., 2008, 68, 8361-8368.
141. Chiarini, F.; Falà, F.; Tazzari, P. L.; Ricci, F.; Astolfi, A.; Pession, A.; Pagliaro, P.; McCubrey, J. A.; Martelli, A. M. Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res., 2009, 69, 3520-3528.
142. Park, S.; Chapuis, N.; Bardet, V.; Tamburini, J.; Gallay, N.; Willems, L.; Knight, Z. A.; Shokat, K. M.; Azar, N.; Viguié, F.; Ifrah, N.; Dreyfus, F.; Mayeux, P.; Lacombe, C.; Bouscary, D. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia, 2008, 22, 1698-1706.
143. Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B. Y. Discovery of (thienopyrimidin-2-yl) aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. J. Med. Chem., 2010, 53, 1086-1097.
144. Heffron, T. P.; Berry, M.; Castanedo, G.; Chang, C.; Chuckowree, I.; Dotson, J.; Folkes, A.; Gunzner, J.; Lesnick, J. D.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Peterson, D.; Salphati, L.; Sampath, D.; Sideris, S.; Sutherlin, D. P.; Tsui, V.; Wan, N. C.; Wang, S.; Wong, S.; Zhu, B. Y. Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor. Bioorg. Med. Chem. Lett., 2010, 20, 2408-2411.
145. Dehnhardt, C. M.; Venkatesan, A. M.; Delos Santos, E.; Chen, Z.; Santos, O.; Ayral-Kaloustian, S.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Chaudhary, I.; Yu, K.; Gibbons, J.; Abraham, R.; Mansour, T. S. Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402. J. Med. Chem., 2010, 53, 798-810.
146. Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Soloveva, V.; Venkatesan, A.; Dehnhardt, C.; Delos Santos, E.; Chen, Z.; Dos Santos, O; Ayral-Kaloustian, S.; Gibbons, J. Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor. Mol. Cancer Ther., 2010, 9, 976-984.
147. Chen, Z.; Venkatesan, A. M.; Dehnhardt, C. M.; Ayral-Kaloustian, S.; Brooijmans, N.; Mallon, R.; Feldberg, L.; Hollander, I.; Lucas, J.; Yu, K.; Kong, F.; Mansour, T. S. Synthesis and SAR of novel 4- morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors. J. Med. Chem., 2010, 53, 3169-3182.
148. Venkatesan, A. M.; Dehnhardt, C. M.; Chen, Z.; Santos, E. D.; 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, 653-656.
149. Cheng, H.; Bagrodia, S.; Bailey, S.; Edwards, M.; Hoffman, J.; Hu, Q.; Kania, R.; Knighton, D. R.; Marx, M. A.; Ninkovic, S.; Sun, S.; Zhang, E. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design. Med. Chem. Commun., 2010, 1, 139-144.
150. Li, T.; Wang, J.; Wang, X.; Yang, N.; Chen, S. M.; Tong, L. J.; Yang, C. H.; Meng, L. H.; Ding, J. WJD008, a dual phosphatidylinositol 3-Kinase (PI3K)/mammalian target of rapamycin inhibitor, prevents pi3k signaling and inhibits the proliferation of transformed cells with oncogenic PI3K mutant. J. Pharmacol. Exp. Ther., 2010, 334, 830-838.
151. Venkatesan, A. M.; Dehnhardt, C. M.; Delos Santos, E.; Chen, Z.; Dos Santos, O.; Ayral-Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Yu, K.; Gibbons, J.; Abraham, R. T.; Chaudhary, I.; Mansour, T. S. Bis (morpholino-1, 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. J. Med. Chem., 2010, 53, 2636-2645.
152. Zhang, N.; Ayral-Kaloustian, S.; Anderson, J. T.; Nguyen, T.; Das, S.; Venkatesan, A. M.; Brooijmans, N.; Lucas, J.; Yu, K.; Hollander, I.; Mallon, R. 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer. Bioorg. Med. Chem. Lett., 2010, 20, 3526-3529.
153. Ayral-Kaloustian, S.; Gu, J.; Lucas, J.; Cinque, M.; Gaydos, C.; Zask, A.; Chaudhary, I.; Wang, J.; Di, L.; Young, M.; Ruppen, M., Mansour, T. S.; Gibbons, J. J.; Yu, K. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates. J. Med. Chem., 2010, 53, 452-459.
154. Sato, T.; Nakashima, A.; Guo, L.; Coffman, K.; Tamanoi, F. Single aminoacid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene, 2010, 29, 2746-2752.
155. Le Tourneau, C.; Faivre, S.; Raymond, E. New developments in multitargeted therapy for patients with solid tumours. Cancer Treat. Rev., 2008, 34, 37-48. (Pubitemid 351168610)
156. Weston, A. D.; Hood, L. Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J. Proteome Res., 2004, 3, 179-196. (Pubitemid 38500984)
157. Butcher, E. C.; Berg, E. L.; Kunkel, E. J. Systems biology in drug discovery. Nat. Biotechnol., 2004, 22, 1253-1259. (Pubitemid 39336778)
158. Tatonetti N. P.; Liu, T.; Altman, R. B. Predicting drug side-effects by chemical systems biology. Genome Biol., 2009, 10, 238.
159. Berger, S. I.; Iyengar, R. Network analyses in systems pharmacology. Bioinformatics, 2009, 25, 2466-2472.