Current development of the second generation of mTOR inhibitors as anticancer agents

Chinese Journal of Cancer

Volumn 31, Issue 1, 2012, Pages 8-18

  Zhou, Hong Yu ^a   Huang, Shi Le ^a  

^a LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

Cancer; Inhibitor; mTOR; Rapalogs; Rapamycin

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; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ABI 009; ANTINEOPLASTIC AGENT; BGT 226; EVEROLIMUS; GNE 477; KU 0063794; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; NAB RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PL 103; PP 242; PP 30; PROTEIN KINASE B; RAPALOG DERIVATIVE; RAPAMYCIN; RAPAMYCIN DERIVATIVE; RIDAFOROLIMUS; TEMSIROLIMUS; TORIN 1; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 600; WJD 008; WORTMANNIN; WYE 354; WYE 687; XL 765;

ACUTE GRANULOCYTIC LEUKEMIA; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; COLON CANCER; COLORECTAL CANCER; DRUG DESIGN; DRUG EFFICACY; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG SPECIFICITY; DRUG TARGETING; ENZYME PHOSPHORYLATION; GASTROINTESTINAL STROMAL TUMOR; GLIOBLASTOMA; GLIOMA; HEMATOLOGIC MALIGNANCY; HUMAN; KIDNEY CARCINOMA; LEUKEMIA; LUNG CANCER; MELANOMA; MONOTHERAPY; MULTIPLE MYELOMA; NEUROENDOCRINE TUMOR; NONHUMAN; OSTEOSARCOMA; OVARY CANCER; PANCREAS CANCER; PANCREAS TUMOR; PROSTATE CANCER; REVIEW; SARCOMA; SIGNAL TRANSDUCTION; SOFT TISSUE SARCOMA;

ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; FURANS; HUMANS; IMIDAZOLES; INDOLES; MORPHOLINES; MULTIPROTEIN COMPLEXES; NAPHTHYRIDINES; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; PURINES; PYRIDINES; PYRIMIDINES; QUINOLINES; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84862912936     PISSN: 1000467X     EISSN: 1944446X     Source Type: Journal    
DOI: 10.5732/cjc.011.10281     Document Type: Review

References (109)

1. 1 progression. Cell, 1993,73(3):585-596.
2. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol, 2003,3(4):371-377.
3. Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell, 2003,12(2):271-280.
4. Seeliger H, Guba M, Kleespies A, et al. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev, 2007,26(3-4):611-621.
5. Chakraborty S, Mohiyuddin SM, Gopinath KS, et al. Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma. BMC Cancer, 2008,8:163.
6. Darb-Esfahani S, Faggad A, Noske A, et al. Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro. J Cancer Res Clin Oncol, 2009,135(7):933-941.
7. Rosenwald IB. The role of translation in neoplastic transformation from a pathologist's point of view. Oncogene, 2004,23(18):3230-3247.
8. Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol, 2004,63(12):1236-1242.
9. Riemenschneider MJ, Betensky RA, Pasedag SM, et al. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Cancer Res, 2006,66(11):5618-5623.
10. Helliwell SB, Wagner P, Kunz J, et al. TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell, 1994,5(1):105-118.
11. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell, 2002,10 (3):457-468.
12. Liu L, Li F, Cardelli JA, et al. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene, 2006,25(53):7029-7040.
13. Fingar DC, 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 (18): 3151-3171.
14. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J, 2008,416(3):375-385.
15. Liu L, Luo Y, Chen L, et al. Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J Biol Chem, 2010,285(49):38362-38373.
16. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol, 2004,6(11):1122-1128.
17. Barilli A, Visigalli R, Sala R, et al. In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc Res, 2008,78(3):563-571.
18. Hernandez-Negrete l, Carretero-Ortega J, Rosenfeldt H, et al. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem, 2007,282 (32): 23708-23715.
19. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 2002,110(2):177-189.
20. Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell, 2003,11 (4):895-904.
21. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell, 2007,25(6):903-915.
22. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol, 2011, 12(1): 21-35.
23. Zhou H, Huang S. The complexes of mammalian target of rapamycin. Curr Protein Pept Sci, 2010,11(6):409-424.
24. Chen J, Zheng XF, Brown EJ, et al. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci U S A, 1995,92 (11):4947-4951.
25. Kunz J, Hall MN. Cyclosporin A, FK506 and rapamycin: more than just immunosuppression. Trends Biochem Sci, 1993,18(9): 334-338.
26. Choi J, Chen J, Schreiber SL, et al. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science, 1996,273(5272):239-242.
27. Oshiro N, Yoshino K, Hidayat S, et al. Dissociation of raptor from mTOR is a mechanism of rapamycin-in duced inhibition of mTOR function. Genes Cells, 2004,9(4):359-366.
28. Edinger AL, Thompson CB. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell, 2002,13(7):2276-2288.
29. Schneider A, Younis RH, Gutkind JS. Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/ REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia, 2008,10(11):1295-1302.
30. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol, 2002,4(9):648-657.
31. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol, 2002,4(9):658-665.
32. Gao X, Zhang Y, Arrazola P, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol, 2002,4(9):699-704.
33. Tee AR, Fingar DC, Manning BD, et al. Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA, 2002,99 (21):13571-13576.
34. Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell, 2003,11(6):1457-1466.
35. Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci, 2003,28(11):573-576.
36. Zhang Y, Gao X, Saucedo LJ, et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol, 2003,5(6):578-581.
37. Stocker H, Radimerski T, Schindelholz B, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol, 2003,5(6):559-565.
38. Price DJ, Grove JR, Calvo V, et al. Rapamycin-in duced inhibition of the 70-kilodalton S6 protein kinase. Science, 1992,257(5072):973-977.
39. Brunn GJ, Hudson CC, Sekulic A, et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science, 1997,277(5322):99-101.
40. Jefferies HB, Reinhard C, Kozma SC, et al. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci USA, 1994,91 (10):4441-4445.
41. Terada N, Patel HR, Takase K, et al. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci USA, 1994,91 (24): 11477-11481.
42. Raught B, Peiretti F, Gingras AC, et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J, 2004,23(8):1761-1769.
43. Shahbazian D, Roux PP, Mieulet V, et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J, 2006,25(12):2781-2791.
44. Holz MK, Ballif BA, Gygi SP, et al. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell, 2005,123(4):569-580.
45. Marcotrigiano J, Gingras AC, Sonenberg N, et al. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell, 1999,3(6):707-716.
46. Pause A, Belsham GJ, Gingras AC, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature, 1994,371(6500):762-767.
47. Hsu PP, Kang SA, Rameseder J, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science, 2011,332(6035): 1317-1322.
48. Yu Y, Yoon SO, Poulogiannis G, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science, 2011,332(6035): 1322-1326.
49. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res, 2006,66(3):1500-1508.
50. Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol, 2006,26(1):63-76.
51. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo), 1975,28(10): 721-726.
52. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo), 1975,28(10):727-732.
53. Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol, 1996,14:483-510.
54. Hosoi H, Dilling MB, Shikata T, et al. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-in dependent apoptosis in human rhabdomyosarcoma cells. Cancer Res, 1999,59(4):886-894.
55. Shi Y, Frankel A, Radvanyi LG, et al. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res, 1995,55(9):1982-1988.
56. Ishizuka T, Sakata N, Johnson GL, et al. Rapamycin potentiates dexamethasone-induced apoptosis and inhibits JNK activity in lymphoblastoid cells. Biochem Biophys Res Commun, 1997,230(2):386-391.
57. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol, 2008,1(1-4):27-36.
58. Rizzieri DA, Feldman E, Dipersio JF, et al. 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 (9):2756-2762.
59. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther, 2007,82(4):381-388.
60. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet, 2008,372(9637):449-456.
61. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol, 2009,27(23):3822-3829.
62. Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med Chem, 2010,10(7):571-581.
63. Yuan R, Kay A, Berg WJ, et al. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol, 2009,2:45.
64. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol, 2009,27 (13):2278-2287.
65. Carew JS, Kelly KR, Nawrocki ST. Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol, 2011,6(1): 17-27.
66. Mondesire WH, Jian W, Zhang H, et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res, 2004,10(20):7031-7042.
67. Sadler TM, Gavriil M, Annable T, et al. Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. Endocr Relat Cancer, 2006,13(3):863-873.
68. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptorindependent pathway that regulates the cytoskeleton. Curr Biol, 2004,14(14):1296-1302.
69. Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol, 2006,16(18):1865-1870.
70. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J, 2007,405(3):513-522.
71. Woo SY, Kim DH, Jun CB, et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem, 2007,282 (35):25604-25612.
72. Martin J, Masri J, Bernath A, et al. Hsp70 associates with Rictor and is required for mTORC2 formation and activity. Biochem Biophys Res Commun, 2008,372(4):578-583.
73. Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005,307(5712):1098-1101.
74. Jones KT, Greer ER, Pearce D, et al. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol, 2009,7(3):e60.
75. Soukas AA, Kane EA, Carr CE, et al. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev, 2009,23(4):496-511.
76. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell, 2006,22(2): 159-168.
77. Liu L, Chen L, Chung J, et al. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene, 2008,27(37):4998-5010.
78. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell, 2007,129(7):1261-1274.
79. Sparks CA, Guertin DA. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene, 2011,29 (26):3733-3744.
80. Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther, 2011,10(3):395-403.
81. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 2008,118(9):3065-3074.
82. Heffron TP, Berry M, Castanedo G, et al. Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor. Bioorg Med Chem Lett, 2010,20(8):2408-2411.
83. Maira SM, Stauffer F, Brueggen J, et al. 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(7):1851-1863.
84. Zou ZQ, Zhang XH, Wang F, et al. 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(1):97-101.
85. Molckovsky A, Siu LL. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology Meeting. J Hematol Oncol, 2008,1: 20.
86. Li T, Wang J, Wang X, et al. 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(3):830-838.
87. Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res, 2011,13(2):R21.
88. Raynaud FI, Eccles S, Clarke PA, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res, 2007,67 (12): 5840-5850.
89. Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/ mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell, 2006,9(5):341-349.
90. Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia, 2008,22(9):1698-1706.
91. Westhoff MA, Kandenwein JA, Karl S, et al. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene, 2009,28(40):3586-3596.
92. Prevo R, Deutsch E, Sampson O, et al. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res, 2008,68 (14):5915-5923.
93. Serra V, Markman B, Scaltriti M, et al. 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(19):8022-8030.
94. Cao P, Maira SM, Garcia-Echeverria C, et al. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer, 2009,100(8):1267-1276.
95. Baumann P, Mandl-Weber S, Oduncu F, et al. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res, 2009,315 (3):485-497.
96. McMillin DW, Ooi M, Delmore J, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res, 2009,69(14):5835-5842.
97. Liu TJ, Koul D, LaFortune T, et al. 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(8):2204-2210.
98. Manara MC, Nicoletti G, Zambelli D, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res, 2010,16 (2):530-540.
99. Burris H, Rodon, J, Sharma, RS, et al. First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors. ASCO. Alexandria, VA: American Society of Clinical Oncology, 2010:3005.
100. Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol, 2009,7(2):e38.
101. Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem, 2009,284(12): 8023-8032.
102. Yu K, Toral-Barza L, Shi C, 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(15): 6232-6240.
103. Garcia-Martinez JM, Moran J, Clarke RG, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J, 2009,421(1):29-42.
104. Hoang B, Frost P, Shi Y, et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood, 2010,116 (22):4560-4568.
105. Chresta CM, Davies BR, Hickson I, et al. 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(1):288-298.
106. Tan DS, Dumez H, Olmos D, et al. First-in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma. ASCO. Alexandria, VA: American Society of Clinical Oncology, 2010:3006.
107. Jessen K, Wang S, Kessler L, et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. AACR. Boston, MA: American Association for Cancer Research, 2009:B148.
108. Jiang Q, Weiss JM, Back T, et al. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res, 2011,71(12):4074-4084.
109. Bhagwat SV, Gokhale PC, Crew AP, et al. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Mol Cancer Ther, 2011, 10(8):1394-406.