Chemistry and pharmacology of rapamycin and its derivatives

Enzymes

Volumn 27, Issue C, 2010, Pages 329-366

  Abraham, Robert T ^a   Gibbons, James J ^a   Graziani, Edmund I ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 77954896543     PISSN: 18746047     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S1874-6047(10)27017-8     Document Type: Chapter

References (213)

1. Sehgal S.N. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003, 35:7S-14S.
2. Sehgal S.N., Baker H., Vezina C. Rapamycin (AY-22, 989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975, 28:727-732.
3. Abraham R.T., Wiederrecht G.J. Immunopharmacology of rapamycin. Annu Rev Immunol 1996, 14:483-510.
4. Sabatini D.M., Erdjument-Bromage H., Lui M., Tempst P., Snyder S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin- dependent fashion and is homologous to yeast TORs. Cell 1994, 78:35-43.
5. Sabers C.J., et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995, 270:815-822.
6. Brown E.J., et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994, 369:756-758.
7. Grube E., Buellesfeld L. Rapamycin analogs for stent-based local drug delivery. Everolimus- and tacrolimus-eluting stents. Herz 2004, 29:162-166.
8. Calne R.Y. The development of immunosuppression: the rapamycin milestone. Transplant Proc 2003, 35:15S-17S.
9. Abraham R.T. PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst) 2004, 3:883-887.
10. Sabatini D.M. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006, 6:729-734.
11. Loewith R., et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002, 10:457-468.
12. Jacinto E., Hall M.N. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003, 4:117-126.
13. Sarbassov D.D., et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006, 22:159-168.
14. Thoreen C.C., et al. An ATP-competitive mTOR inhibitor reveals rapamycin-insensitive functions of mTORC1. J Biol Chem 2009, 284:8023-8032.
15. Peterson T.R., et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009, 137:873-886.
16. Chiang G.G., Abraham R.T. Targeting the mTOR signaling network in cancer. Trends Mol Med 2007, 13:433-442.
17. Kim D.H., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110:163-175.
18. Fingar D.C., Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004, 23:3151-3171.
19. Gingras A.C., Raught B., Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001, 15:807-826.
20. Sancak Y., et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 320:1496-1501.
21. Manning B.D., Cantley L.C. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 2003, 31:573-578.
22. Manning B.D., Cantley L.C. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 2003, 28:573-576.
23. Morice W.G., Brunn G.J., Wiederrecht G., Siekierka J.J., Abraham R.T. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem 1993, 268:3734-3738.
24. Nourse J., et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 1994, 372:570-573.
25. Guertin D.A., Sabatini D.M. The pharmacology of mTOR inhibition. Sci Signal 2009, 2:pe24.
26. 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.
27. Stan R., McLaughlin M.M., Cafferkey R., Johnson R.K., Rosenberg M., Livi G.P. Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. J Biol Chem 1994, 269:32027-32030.
28. Leone M., et al. The FRB domain of mTOR: NMR solution structure and inhibitor design(,). Biochemistry 2006, 45:10294-10302.
29. Shor B., et al. 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.
30. Edinger A.L., Linardic C.M., Chiang G.G., Thompson C.B., Abraham R.T. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 2003, 63:8451-8460.
31. Bjornsti M.A., Houghton P.J. The tor pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4:335-348.
32. Petroulakis E., Mamane Y., Le Bacquer O., Shahbazian D., Sonenberg N. mTOR signaling: implications for cancer and anticancer therapy. Br J Cancer 2007, 96(Suppl):R11-R15.
33. Rubinsztein D.C., Gestwicki J.E., Murphy L.O., Klionsky D.J. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007, 6:304-312.
34. Noda T., Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 1998, 273:3963-3966.
35. Lum J.J., DeBerardinis R.J., Thompson C.B. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005, 6:439-448.
36. Hoyer-Hansen M., Jaattela M. Autophagy: an emerging target for cancer therapy. Autophagy 2008, 4:574-580.
37. Jin S., White E. Role of autophagy in cancer: management of metabolic stress. Autophagy 2007, 3:28-31.
38. Meijer A.J., Codogno P. Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci 2009, 46:210-240.
39. Meijer A.J., Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 2004, 36:2445-2462.
40. Chang Y.Y., Neufeld T.P. An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 2009, 20:2004-2014.
41. Jung C.H., et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009, 20:1992-2003.
42. Swindells D.C.N., White P.S., Findlay J.A. The x-ray crystal structure of rapamycin, c51h91no13. Can J Chem 1978, 56:2491-2492.
43. Findlay J.A., Radics L. On the chemistry and high field nuclear magnetic resonance spectroscopy of rapamycin. Can J Chem 1980, 58:579-590.
44. Schwecke T., et al. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 1995, 92:7839-7843.
45. Sattely E.S., Fischbach M.A., Walsh C.T. Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways. Nat Prod Rep 2008, 25:757-793.
46. Fischbach M.A., Walsh C.T. Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms. Chem Rev 2006, 106:3468-3496.
47. Staunton J., Wilkinson B. Biosynthesis of erythromycin and rapamycin. Chem Rev 1997, 97:2611-2630.
48. Kino T., et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987, 40:1249-1255.
49. Hatanaka H., et al. FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1988, 41:1592-1601.
50. Arai T., Kouama Y., Suenaga T., Honda H. Ascomycin, an antifungal antibiotic. J Antibiot (Tokyo) 1962, 15:231-232.
51. Harding M.W., Galat A., Uehling D.E., Schreiber S.L. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 1989, 341:758-760.
52. Fretz H., Albers M.W., Galat A., Standaert R.F., Lane W.S., Burakoff S.J. Rapamycin and FK506 binding proteins (immunophilins). J Am Chem Soc 1991, 113:1409-1411.
53. Edlich F., Fischer G. Pharmacological targeting of catalyzed protein folding: the example of peptide bond cis/trans isomerases. Handb Exp Pharmacol 2006, 359-404.
54. Lam E., et al. A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor. J Biol Chem 1995, 270:26511-26522.
55. Sinkins W.G., Goel M., Estacion M., Schilling W.P. Association of immunophilins with mammalian TRPC channels. J Biol Chem 2004, 279:34521-34529.
56. Cameron A.M., Steiner J.P., Sabatini D.M., Kaplin A.I., Walensky L.D., Snyder S.H. Immunophilin FK506 binding protein associated with inositol 1, 4, 5-trisphosphate receptor modulates calcium flux. Proc Natl Acad Sci USA 1995, 92:1784-1788.
57. Shim S., et al. Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening. Neuron 2009, 64:471-483.
58. Ratajczak T., Ward B.K., Minchin R.F. Immunophilin chaperones in steroid receptor signalling. Curr Top Med Chem 2003, 3:1348-1357.
59. Jin Y.J., Burakoff S.J. The 25-kDa FK506-binding protein is localized in the nucleus and associates with casein kinase II and nucleolin. Proc Natl Acad Sci USA 1993, 90:7769-7773.
60. Chambraud B., Belabes H., Fontaine-Lenoir V., Fellous A., Baulieu E.E. The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation. FASEB J 2007, 21:2787-2797.
61. Edlich F., et al. The specific FKBP38 inhibitor N-(N', N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. J Biol Chem 2006, 281:14961-14970.
62. Salituro G.M., et al. Meridamycin: a novel nonimmunosuppressive FKBP12 ligand from Streptomyces hygroscopicus. Tetrahedron Lett 1995, 36:997-1000.
63. Fehr T., et al. Antascomicins A, B, C, D and E. Novel FKBP12 binding compounds from a Micromonospora strain. J Antibiot (Tokyo) 1996, 49:230-233.
64. Summers M.Y., Leighton M., Liu D., Pong K., Graziani E.I. 3-normeridamycin: a potent non-immunosuppressive immunophilin ligand is neuroprotective in dopaminergic neurons. J Antibiot (Tokyo) 2006, 59:184-189.
65. Van Duyne G.D., Standaert R.F., Schreiber S.L., Clardy J. Atomic structure of the rapamycin human immunophilin FKBP-12 complex. J Am Chem Soc 1991, 113:7433-7434.
66. Heitman J., Movva N.R., Hall M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991, 253:905-909.
67. Liu J., Farmer J.D., Lane W.S., Friedman J., Weissman I., Schreiber S.L. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991, 66:807-815.
68. Griffith J.P., et al. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 1995, 82:507-522.
69. Luengo J.I., et al. Structure-activity studies of rapamycin analogs: evidence that the C-7 methoxy group is part of the effector domain and positioned at the FKBP12-FRAP interface. Chem Biol 1995, 2:471-481.
70. Banaszynski L.A., Liu C.W., Wandless T.J. Characterization of the FKBP.rapamycin.FRB ternary complex. J Am Chem Soc 2005, 127:4715-4721.
71. Kallen J.A., Sedrani R., Cottens S. X-ray crystal structure of 28-O-methylrapamycin complexed with FKBP12: is the cyclohexyl moiety part of the effector domain of rapamycin?. J Am Chem Soc 1996, 118:5857-5861.
72. Sedrani R., Jones L.H., Jutzi-Eme A.M., Schuler W., Cottens S. Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity. Bioorg Med Chem Lett 1999, 9:459-462.
73. Caufield C.E. Structure-activity relationships involving modifications to the macrolides FK-506 and rapamycin. Curr Pharm Des 1995, 1:145-160.
74. Punt C.J., Boni J., Bruntsch U., Peters M., Thielert C. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 2003, 14:931-937.
75. Kirchner G.I., Meier-Wiedenbach I., Manns M.P. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004, 43:83-95.
76. Chen Y.W., et al. Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol 2007, 49:228-235.
77. Palaparthy R., et al. Pharmacokinetics and safety of ABT-578, a sirolimus (rapamycin) analogue, after single intravenous bolus injection in healthy male volunteers. Clin Drug Investig 2005, 25:491-498.
78. Karyekar C.S., et al. A phase I multiple-dose escalation study characterizing pharmacokinetics and safety of ABT-578 in healthy subjects. J Clin Pharmacol 2005, 45:910-918.
79. Mita M.M., et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5days every 2weeks to patients with advanced malignancies. J Clin Oncol 2008, 26:361-367.
80. Dickman D.A., et al. Antifungal rapamycin analogues with reduced immunosuppressive activity. Bioorg Med Chem Lett 2000, 10:1405-1408.
81. Wagner R., et al. Rapamycin analogs with reduced systemic exposure. Bioorg Med Chem Lett 2005, 15:5340-5343.
82. Nicolaou K.C., Chakraborty T.K., Piscopio A.D., Minowa N., Bertinato P. Total synthesis of rapamycin. J Am Chem Soc 1993, 115:4419-4420.
83. Romo D., Meyer S.D., Johnson D.D., Schreiber S.L. Total synthesis of (-)-rapamycin using an Evans-Tishchenko fragment coupling. J Am Chem Soc 1993, 115:7906-7907.
84. Hayward C.M., Yohannes D., Danishefsky S.J. Total synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction. J Am Chem Soc 1993, 115:9345-9346.
85. Smith I.A.B., Condon S.M., McCauley J.A., Leazer J.L., Leahy J.W., Maleczka R.E. Total synthesis of rapamycin and demethoxyrapamycin. J Am Chem Soc 1995, 117:5407-5408.
86. Nicolaou K.C., Anthony D.P., Peter B., Tushar K.C., Nobuto M., Kazunori K. Total synthesis of rapamycin. Chemistry-A Eur J 1995, 1:318-333.
87. Maddess M.L., et al. Total synthesis of rapamycin. Angew Chem Int Ed Engl 2007, 46:591-597.
88. Ley S.V., et al. Total synthesis of rapamycin. Chemistry 2009, 15:2874-2914.
89. Graziani E.I., et al. Novel sulfur-containing rapamycin analogs prepared by precursor-directed biosynthesis. Org Lett 2003, 5:2385-2388.
90. Ritacco F.V., et al. Production of novel rapamycin analogs by precursor-directed biosynthesis. Appl Environ Microbiol 2005, 71:1971-1976.
91. Nishida H., et al. Generation of novel rapamycin structures by microbial manipulations. J Antibiot (Tokyo) 1995, 48:657-666.
92. Khaw L.E., Bohm G.A., Metcalfe S., Staunton J., Leadlay P.F. Mutational biosynthesis of novel rapamycins by a strain of Streptomyces hygroscopicus NRRL 5491 disrupted in rapL, encoding a putative lysine cyclodeaminase. J Bacteriol 1998, 180:809-814.
93. Gregory M.A., et al. Isolation and characterization of pre-rapamycin, the first macrocyclic intermediate in the biosynthesis of the immunosuppressant rapamycin by S. hygroscopicus. Angew Chem Int Ed Engl 2004, 43:2551-2553.
94. Gregory M.A., et al. Mutasynthesis of rapamycin analogues through the manipulation of a gene governing starter unit biosynthesis. Angew Chem Int Ed Engl 2005, 44:4757-4760.
95. Gregory M.A., et al. Rapamycin biosynthesis: elucidation of gene product function. Org Biomol Chem 2006, 4:3565-3568.
96. Goss R.J., Lanceron S.E., Wise N.J., Moss S.J. Generating rapamycin analogues by directed biosynthesis: starter acid substrate specificity of mono-substituted cyclohexane carboxylic acids. Org Biomol Chem 2006, 4:4071-4073.
97. Steiner J.P., et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med 1997, 3:421-428.
98. Gold B.G., Densmore V., Shou W., Matzuk M.M., Gordon H.S. Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J Pharmacol Exp Ther 1999, 289:1202-1210.
99. Sharkey J., Butcher S.P. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 1994, 371:336-339.
100. Bocquet A., et al. Failure of GPI compounds to display neurotrophic activity in vitro and in vivo. Eur J Pharmacol 2001, 415:173-180.
101. Ruan B., et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc Natl Acad Sci USA 2008, 105:33-38.
102. Wiederrecht G.J., Sabers C.J., Brunn G.J., Martin M.M., Dumont F.J., Abraham R.T. Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog Cell Cycle Res 1995, 1:53-71.
103. Eng C.P., Sehgal S.N., Vézina C. Activity of rapamycin (AY-22, 989) against transplanted tumors. J Antibiot (Tokyo) 1984, 37:1231-1237.
104. Dilling M.B., Dias P., Shapiro D.N., Germain G.S., Johnson R.K., Houghton P.J. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor. Cancer Res 1994, 54:903-907.
105. Dancey J., Sausville E.A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2003, 2:296-313.
106. Garber K. Rapamycin's resurrection: a new way to target the cancer cell cycle. J Natl Cancer Inst 2001, 93:1517-1519.
107. Dancey J.E. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 2005, 14:313-328.
108. Inoki K., Li Y., Zhu T., Wu J., Guan K.-L. TSC2 is phosphorylated and inhibited by AKT and suppresses mTOR signaling. Nat Cell Biol 2002, 4:648-657.
109. Goncharova E.A., et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. J Biol Chem 2002, 277:30958-30967.
110. Manning B.D., Tee A.R., Logsdon M.N., Blenis J., Cantley L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol Cell 2002, 10:151-162.
111. Potter C.J., Pedraza L.G., Xu T. AKT regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002, 4:658-665.
112. Li Y., Corradetti M.N., Inoki K., Guan K.L. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci 2004, 29:32-38.
113. Long X., Lin Y., Ortiz-Vega S., Yonezawa K., Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005, 15:702-713.
114. Yuan T.L., Cantley L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008, 27:5497-5510.
115. Inoki K., Corradetti M.N., Guan K.L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005, 37:19-24.
116. Keniry M., Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 2008, 27:5477-5485.
117. Chalhoub N., Baker S.J. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009, 4:127-150.
118. Makowski L., Hayes D.N. Role of LKB1 in lung cancer development. Br J Cancer 2008, 99:683-688.
119. Lu K.H., et al. Loss of tuberous sclerosis complex-2 function and activation of Mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 2008, 14:2543-2550.
120. Ma X.M., Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009, 10:307-318.
121. Proud C.G. mTORC1 signalling and mRNA translation. Biochem Soc Trans 2009, 37:227-231.
122. Gingras A.C., Raught B., Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999, 68:913-963.
123. Sonenberg N. eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. Biochem Cell Biol 2008, 86:178-183.
124. Beretta L., Gingras A.C., Svitkin Y.V., Hall M.N., Sonenberg N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 1996, 15:658-664.
125. Brunn G.J., et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997, 277:99-101.
126. Lazaris-Karatzas A., Montine K.S., Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 1990, 345:544-547.
127. De Benedetti A., Graff J.R. eIF-4E expression and its role in malignancies and metastases. Oncogene 2004, 23:3189-3199.
128. Hashemolhosseini S., Nagamine Y., Morley S.J., Desrivières S., Mercep L., Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 1998, 273:14424-14429.
129. Thomas G.V., et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006, 12:122-127.
130. Zhong H., et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000, 60:1541-1545.
131. Semenza G.L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 2009, 19:12-16.
132. Guba M., et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002, 8:128-135.
133. Kim W.Y., Kaelin W.G. Role of VHL gene mutation in human cancer. J Clin Oncol 2004, 22:4991-5004.
134. Mills J.R., et al. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci USA 2008, 105:10853-10858.
135. Wangpaichitr M., et al. Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 2008, 591:124-127.
136. Yan H., et al. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 2006, 66:2305-2313.
137. Dan H.C., Cooper M.J., Cogswell P.C., Duncan J.A., Ting J.P., Baldwin A.S. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008, 22:1490-1500.
138. Wei G., et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 2006, 10:349-351.
139. Huang J., Manning B.D. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009, 37:217-222.
140. 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.
141. Tremblay F., Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001, 276:38052-38060.
142. O'Reilly K.E., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66:1500-1508.
143. Um S.H., et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004, 431:200-205.
144. Guertin D.A., et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009, 15:148-159.
145. Nardella C., et al. Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis. Sci Signal 2009, 2:ra2.
146. Shaw R.J., Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006, 441:424-430.
147. Deberardinis R.J., Lum J.J., Hatzivassiliou G., Thompson C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008, 7:11-20.
148. Anjum R., Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 2008, 9:747-758.
149. Silva R.L., Wendel H.G. MNK, EIF4E and targeting translation for therapy. Cell Cycle 2008, 7:553-555.
150. van Gorp A.G.M., et al. AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene 2008, 28:95-106.
151. Ballif B.A., Roux P.P., Gerber S.A., MacKeigan J.P., Blenis J., Gygi S.P. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc Natl Acad Sci USA 2005, 102:667-672.
152. von Gise A., et al. Apoptosis suppression by Raf-1 and MEK1 requires MEK-and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 2001, 21:2324-2336.
153. She Q.-B., Solit D.B., Ye Q., O'Reilly K.E., Lobo J., Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005, 8:287-297.
154. Lasithiotakis K.G., et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Invest Dermatol 2008, 128:2013-2023.
155. Bertrand F.E., Spengemen J.D., Shelton J.G., McCubrey J.A. Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 2005, 19:98-102.
156. Yu K., Toral-Barza L., Shi C., Zhang W.G., Zask A. Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategy. Cancer Biol Ther 2008, 7:307-315.
157. Kinkade C.W., et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008, 118:3003-3006.
158. Robert F., Pelletier J. Translation initiation: a critical signalling node in cancer. Expert Opin Ther Targets 2009, 13:1279-1293.
159. Dang C.V. The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found Symp Proc 2007, 4:35-53.
160. Balakumaran B.S., et al. MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. Cancer Res 2009, 69:7803-7810.
161. Hudes G., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356:2271-2281.
162. Motzer R.J., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008, 372:449-456.
163. Meric-Bernstam F., Gonzalez-Angulo A.M. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009, 27:2278-2287.
164. Hait W.N. Targeted cancer therapeutics. Cancer Res 2009, 69:1263-1267.
165. Pantuck A.J., Thomas G., Belldegrun A.S., Figlin R.A. Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications. Semin Oncol 2006, 33:607-613.
166. Dutcher J., et al. Effect of temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 2009, 26:202-209.
167. Migliore C., Giordano S. Molecular cancer therapy: can our expectation be MET?. Eur J Cancer 2008, 44:641-651.
168. Bratslavsky G., Sudarshan S., Neckers L., Linehan W.M. Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res 2007, 13:4667-4671.
169. Merchan J.R., et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: phase I safety and activity results. J Clin Oncol (Meeting Abstracts) 2007, 25:5034.
170. Rini B.I., Atkins M.B. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 2009, 10:992-1000.
171. Hansen A., Boshoff C., Lagos D. Kaposi sarcoma as a model of oncogenesis and cancer treatment. Expert Rev Anticancer Ther 2007, 7:211-220.
172. Stallone G., et al. ID2-VEGF-related pathways in the pathogenesis of Kaposi's sarcoma: a link disrupted by rapamycin. Am J Transplant 2009, 9:558-566.
173. Hess G., et al. Phase III study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigator's choice therapy. J Clin Oncol (Meeting Abstracts) 2008, 26:8513.
174. Costa L.J. Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin's lymphoma. Cancer Treat Rev 2007, 33:78-84.
175. Dal Col J., et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008, 111:5142-5151.
176. Hipp S., Ringshausen I., Oelsner M., Bogner C., Peschel C., Decker T. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 2005, 90:1433-1434.
177. Yazbeck V.Y., et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol 2008, 36:443-450.
178. Zacharek S.J., Xiong Y., Shumway S.D. Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer Res 2005, 65:11354-11360.
179. Oza A.M., et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer-NCIC IND 160. J Clin Oncol 2006, 24:3003.
180. 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.
181. Delmonte A., Sessa C. Molecule-targeted agents in endometrial cancer. Curr Opin Oncol 2008, 20:554-559.
182. Weinstein I.B., Joe A.K. Mechanisms of disease: oncogene addiction-a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006, 3:448-457.
183. Abraham R.T., Gibbons J.J. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007, 13:3109-3114.
184. Hosoi H., et al. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 1999, 59:886-894.
185. Boni J., Burns J., Hug B., Sonnichsen D. mTOR inhibition following a single intravenous infusion of temsirolimus in healthy individuals. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2007, San Francisco, CA.
186. Atkins M.B., et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004, 22:909-918.
187. Patursky-Polischuk I., et al. The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner. Mol Cell Biol 2009, 29:640-649.
188. Feldman M.E., et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009, 7:e38.
189. Thoreen C.C., et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009, 284:8023-8032.
190. García-Martínez J.M., et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 2009, 421:29-42.
191. Yu K., et al. 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.
192. Tremblay F., et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005, 54:2674-2684.
193. 1 events and the regulation of cell proliferation. Science 1989, 246:603-640.
194. Schreiber S.L., Crabtree G.R. The mechanism of action of cyclosporin A and FK506. [Review]. Immunol Today 1992, 13:136-142.
195. Thomson A.W., Turnquist H.R., Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009, 9:324-337.
196. Weichhart T., Saemann M.D. The multiple facets of mTOR in immunity. Trends Immunol 2009, 30:218-226.
197. Zhou L., Chong M.M., Littman D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009, 30:646-655.
198. Feuerer M., Hill J.A., Mathis D., Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 2009, 10:689-695.
199. Haxhinasto S., Mathis D., Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 2008, 205:565-574.
200. Sauer S., et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008, 105:7797-7802.
201. Bensinger S.J., et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004, 172:5287-5296.
202. Basu S., Golovina T., Mikheeva T., June C.H., Riley J.L. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol 2008, 180:5794-5798.
203. Granucci F., Zanoni I., Ricciardi-Castagnoli P. Central role of dendritic cells in the regulation and deregulation of immune responses. Cell Mol Life Sci 2008, 65:1683-1697.
204. Pulendran B. Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 2004, 199:227-250.
205. Jagannath C., Lindsey D.R., Dhandayuthapani S., Xu Y., Hunter R.L., Eissa N.T. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 2009, 15:267-276.
206. Araki K., et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009, 460:108-112.
207. Campisi J., Yaswen P. Aging and cancer cell biology, 2009. Aging Cell 2009, 8:221-225.
208. Fontana L. The scientific basis of caloric restriction leading to longer life. Current Opinion in Gastroenterology 2009, 25:144-150. 110.1097/MOG.1090b1013e32831ef32831ba.
209. Polak P., Hall M.N. mTOR and the control of whole body metabolism. Curr Opin Cell Biol 2009, 21:209-218.
210. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
211. Harrison D.E., et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460:392-395.
212. Selman C., et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009, 326:140-144.
213. Hotamisligil G.S., Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008, 8:923-934.