Current and future directions in mammalian target of rapamycin inhibitors development

Expert Opinion on Investigational Drugs

Volumn 20, Issue 3, 2011, Pages 381-394

  Fasolo, Angelica ^a   Sessa, Cristiana ^b  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b ONCOLOGY INSTITUTE OF SOUTHERN SWITZERLAND   (Switzerland)

Author keywords

dual kinase PI3K mTOR inhibitors; mammalian target of rapamycin; mTORC1 mTORC2 inhibitors; rapalogs; renal cell carcinoma

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ALPHA INTERFERON; AZD 8055; BEVACIZUMAB; BGT 226; ERLOTINIB; EVEROLIMUS; GDC 0980; GSK 2126458; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OSI 027; PF 04691502; PKI 587; RIDAFOROLIMUS; SORAFENIB; SUNITINIB; TEMOZOLOMIDE; TEMSIROLIMUS; UNCLASSIFIED DRUG; XL 765;

ADVANCED CANCER; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ASTHENIA; BLADDER CANCER; BREAST CANCER; COWDEN SYNDROME; DEPRESSION; DIARRHEA; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG ERUPTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DYSPNEA; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; ENZYME PHOSPHORYLATION; FATIGUE; GLIOBLASTOMA; HEAD AND NECK CANCER; HEMATOLOGIC MALIGNANCY; HODGKIN DISEASE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRANSAMINASEMIA; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; LYMPHOMA; MANTLE CELL LYMPHOMA; MAXIMUM PLASMA CONCENTRATION; MELANOMA; METASTASIS; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NAUSEA; NEUROENDOCRINE TUMOR; NEUTROPENIA; NONHODGKIN LYMPHOMA; NONHUMAN; OSTEOSARCOMA; OVARY CANCER; OVERALL SURVIVAL; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PNEUMONIA; PROGRESSION FREE SURVIVAL; PROSTATE CANCER; RECOMMENDED DRUG DOSE; REVIEW; SOFT TISSUE SARCOMA; SOLID TUMOR; STOMACH CANCER; STOMATITIS; THROMBOCYTOPENIA; TREATMENT RESPONSE; TUMOR REGRESSION; VOMITING;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE III AS TOPIC; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 79951627404     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.2011.541154     Document Type: Review

References (100)

1. Huang S, Bjornsti M, Houghton PJ. Rapamycins. Mechanism of action and cellular resistance. Cancer Biol Ther 2003;2:222-32
2. Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs 2008;17:1717-34
3. Tee AR, Manning BD, Roux PP, et al. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signalling by acting as a CTPase-activating (Pubitemid 36953298)
4. Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat Rev Cancer 2010;10:254-66
5. Strimpakos AS, Karapangiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 2009;35:148-59
6. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22 (Pubitemid 47001784)
7. O'Reilly KE, Rojo F, She Q, et al. mTOR inhibition induces upstream receptor kinase signalling and activates Akt. Cancer Res 2006;66:1500-8 (Pubitemid 43259931)
8. Dancey J. mTOR signalling and drug development. J Nat Rev Clin Oncol 2010;7:209-19
9. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83
10. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;8:550-62
11. Chen J, Zheng XF, Brown EJ, Schreiber SL. 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 USA 1995;92:4947-51
12. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12- rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239-42 (Pubitemid 26285890)
13. Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS Motif-mediated Raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003;13:797-806 (Pubitemid 36573247)
14. Nojima H, Tokunaga C, Eguchi S, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signalling (TOS) motif. J Biol Chem 2003;278:15461-4 (Pubitemid 36799651)
15. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol 2008;1:27-36
16. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006;6:729-34 (Pubitemid 44286004)
17. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signalling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007;13:3109-14 (Pubitemid 46944891)
18. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/ PKB. Mol Cell 2006;22:159-68
19. Choo AY, Blenis J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009;8:567-72
20. Yu K, Shi C, Toral-Barza L, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 2010;70:621-31
21. Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38
22. Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358-64 (Pubitemid 43936934)
23. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009;2:pe24
24. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009;8:3831-7
25. Yuan R. Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009;2:45
26. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004;22:2336-47 (Pubitemid 41115390)
27. Fetterly GJ, Mita MM, Britten CD, et al. Pharmacokinetics of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008;26:abstract 14555
28. Mita MM, Britten CD, Poplin E, et al. Deforolimus trial 106-a phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008;26:Abstract 3509
29. Coppin C. Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Biologics 2010;4:91-101
30. Mita MM, Mita AC, Chu QS, et al. 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;26:361-7 (Pubitemid 351171685)
31. Sleijfer S, Wiemer E. Dose selection in phase I studies: why we should always go for the top. J Clin Oncol 2008;26:1576-8
32. O'Donnell A, Faivre S, Burris HA III, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95
33. Tanaka C, O'Reilly T, Kovarik JM, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008;26:1596-602
34. Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26:1603-10
35. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008;14:4726-34
36. Kondo K, Klco J, Nakamura E, et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237-46 (Pubitemid 41039148)
37. Maranchie JK, Vasselli JR, Riss J, et al. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002;1:247-55 (Pubitemid 41039149)
38. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 1998;8:588-94 (Pubitemid 28477364)
39. Erler JT, Cawthorne CJ, Williams KJ, et al. Hypoxia-mediated down regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and independent mechanisms and contributes to drug resistance. Mol Cell Biol 2004;24:2875-89 (Pubitemid 38381277)
40. Unruh A, Ressel A, Mohamed HG, et al. The hypoxia-inducible factor-1alpha is a negative factor for tumor therapy. Oncogene 2003;22:3213-20 (Pubitemid 36712933)
41. Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997;94:8104-9 (Pubitemid 27343784)
42. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Anti-angiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549-54 (Pubitemid 43927103)
43. Mayerhofer M, Aichberger KJ, Florian S, et al. Identification of mTOR as a novel bifunctional target in chronic myeloid leukaemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J 2005;19:960-2 (Pubitemid 40827717)
44. Wan X, Shen N, Mendoza A, et al. CCI-779 inhibits rhabdomiosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/HIF-1alpha/VEGF signalling. Neoplasia 2006;8:394-401 (Pubitemid 43830746)
45. Furge KA, Mackeigan JP, Teh BT. Kinase targets in renal-cell carcinomas:reassessing the old and discovering the new. Lancet Oncol 2010;11:571-8
46. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006;12:5755-63 (Pubitemid 44629606)
47. Peralba JM, Degraffenried L, Friedrichs W, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 2003;9:2887-92 (Pubitemid 36993245)
48. Chang SM, Kuhn J, Wen P, et al. Phase I/Pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 2004;22:427-35 (Pubitemid 39619819)
49. Atkins MB, Hidalgo M, Stadler WM, 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;22:909-18 (Pubitemid 41103603)
50. Hudes G, Carducci M, Tomczak P, et al. for the Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81 (Pubitemid 46849157)
51. Dutcher JP, Szczylik C, Tannir N, et al. Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN). J Clin Oncol 2007:25:abstract 5033
52. NCT00631371: Study Comparing Bevacizumab + Temsirolimus Vs Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects. Available from: http://www. clinicaltrials.gov [Accessed 15 July 2009]
53. Amato RJ, Jac J, Giessinger S, et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009;115:2438-46
54. Motzer RJ, Escudier B, Oudard S, et al.; for the RECORD-1 Study GroupEfficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56
55. Motzer R, Escudier B, Oudard S, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus placebo in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium. Abstract 278
56. De Reijke TM, Bellmunt J, van Poppel H, et al. EORTC-GU group expert opinion on metastatic renal cell cancer. Eur J Cancer 2009;45:765-73
57. Soulieres D. Review of guidelines on the treatment of metastatic renal cell carcinoma. Curr Oncol 2009;16(S1):S67-70
58. Escudier B, Kataja V. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20(S4):iv81-2
59. NCT00719264: Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab in Adult Patients With Kidney Cancer (L2201). Available from: http://www. clinicaltrials.gov [Accessed 11 August 2009]
60. NCT00903175: Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-Line and Second-Line Treatment of Patients With Metastatic Renal Cell Carcinoma (RECORD3). Available from: http://www.clinicaltrials.gov [Accessed 21 July 2009]
61. Bertoni F, Zucca E, Cotter FE. Molecular basis of mantle cell lymphoma. Br J Haematol 2004;124:130-40 (Pubitemid 38122184)
62. Dal Col J, Zancai P, Terrin L, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008;111:5142-51
63. Ansell SM, Inwards DJ, Rowland KM, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma. A phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008;113:508-14
64. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator's choice of therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009;27:3822-9
65. Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in non-mantle cell non-hodgkin's lymphoma subtypes: the University of Chicago Phase II Consortium. J Clin Oncol 2010;28:1-7
66. Gligorov J, Azria D, Namer M, et al. Novel therapeutic strategies combining antihormonal and biological targeted therapies in breast cancer: Focus on clinical trials and perspectives. Crit Rev Hematol Oncol 2007;64:115-28 (Pubitemid 47496223)
67. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 2008;27:5527-41
68. Janes MR, Fruman DA. Targeting TOR dependence in cancer. Oncotarget 2010;1:69-76
69. 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;69:6232-40
70. Di Nicolantonio F, Arena S, Tabernero J, et al. Deragulation of the PI3K and KRAS signalling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010;8:2858-6
71. Garcia-Echeverria, Sellers C. Drug discovery approaches targheting the PI3K/Akt pathway in cancer. Oncogene 2008;27:5511-26
72. Brachmann S, Fritsch C, Maira SM, Garcia-Echeverria C. PI3K and mTOR inhibitors - a new generation of targeted anticancer agents. Curr Opin Cell Biol 2009;21:194-8
73. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signalling and activates Akt. Cancer Res 2006;66:1500-8 (Pubitemid 43259931)
74. Foukas LC, Claret M, Okkenhaug K, et al. Critical role for the p110a phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006;441:366-70 (Pubitemid 44050203)
75. Vanhaesebroeck B, Leevers S J, Ahmadi K, et al. "Synthesis and function of 3-phosphorylated inositol lipids," Annual Rev Biochem 2001;70:535-602 (Pubitemid 32662219)
76. 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;70:288-98
77. 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. Proc Am Soc Clin Oncol 2010;28:3006
78. Papadopoulos KP, Markman B, Tabernero J, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD)of a novel PI3K inhibitor, XL765, administered orally to patients with advanced solid tumors. Proc Am Soc Clin Oncol 2008;26:3510
79. Nghiemphu PL, Omuro AM, Cloughesy T, et al. A phase I safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/ TORC2 inhibitor, in combination with temozolomide (TMZ) in patients with newly diagnosed malignant glioma. Proc Am Soc Clin Oncol 2010;28:3085
80. Cohen RB, Janne PA, Engelman JA, et al. A phase I safety and pharmacokinetic study of PI3K/TORC1/ TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2010;28:3015
81. Brana I, LoRusso P, Baselga J, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/ TORC2 inhibitor administered orally to patients with advanced malignancies. Proc Am Soc Clin Oncol 2010;28:3030
82. Venkatesan AM, Dehnhardt CM, Santos ED, et al. 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;53:2636-45
83. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidilynositol 3-kinase/ mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008;7:1851-63
84. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signalling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008;68:8022-30
85. Burris H, Rodon J, Sharma S, et al. Firs-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients with advanced solid tumors. J Clin Oncol 2010;28:3005
86. NCT00600275 A Phase I/II, Multi-center, Open-label Study of BGT226, Administered Orally in Adult Patients With Advanced Solid Malignancies Including Patients With Advanced Breast Cancer. Available from: http://www. clinicaltrials.gov [Accessed 11 January 2008]
87. Garlich JR, De P, Dey N, et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008;68:206-15 (Pubitemid 351380122)
88. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994;269:5241-8
89. Nutley BP, Raynaud FI, Hayes A, et al. Pharmacokinetics and metabolism of the phospatidylinositol 3-kinase inhibitor LY294002 in the mouse. Proc Am Assoc Cancer Res 2001;92:380
90. Hu L, Zaloudek C, Mills GB, et al. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 2000;6:880-6 (Pubitemid 30159344)
91. Su JD, Mayo LD, Donner DB, Durden DL. PTEN and phosphatidylinositol 3-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res 2003;63:3585-92 (Pubitemid 36793039)
92. Chiorean EG, Mahadevan D, Harris WB, et al. Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly iv in patients with refractory solid tumors. J Clin Oncol 2009;27:2558
93. Silberman J, Dalbey K, Torre C, et al. A novel pan-PI3K/Akt inhibitor, SF1126, inhibits in vitro growth of multiple myeloma cells. Blood (ASH Annual Meeting Abstracts) 2007;110:4806
94. David E, Peng X, Barwick BG, et al. SF1126, a novel PI3K inhibitor results in downstream inhibition of the PI3K axis and displays dequence specific synergy when combined with bortezomib in multiple myeloma cells. Blood (ASH Annual Meeting Abstracts) 2008;112:5167
95. Lonial S, Harvey RD, Francis D, et al. Preliminary results of a phase I study of the pan-PI3K kinase inhibitor SF1126 in patients with relapsed and refractory mieloma. Blood (ASH Annual Meeting Abstracts) 2009;114:3879
96. NCT00927823 A Phase 1, Open-Label, Dose-Escalation Study To Evaluate Safety, Pharmacokinetics, And Pharmacodynamics Of The PI3K/ MTOR Inhibitor PF-04691502 In Adult Patients With Advanced Malignant Solid Tumors. Available from: http://www. clinicaltrials.gov [Accessed 23 June 2009]
97. Cheng H, Bagrodia S, Bailey, et al. Discovery of the highly potent PI3K/ mTOR dual inhibitor PF-04691502 through structure based drug design. Med Chem Commun 2010;1:139-44
98. Dolly S, Wagner AJ, Bendell JC, et al. A firs-in-human, phase I study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advanced solid tumors or non-Hodgkin's lymphoma. J Clin Oncolol 2010;28:3079
99. Knight SD, Adams ND, Burgess JL, et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med Chem Lett 2010;1:39-43
100. NCT00972686: A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK2126458 in Subjects With Solid Tumors or Lymphoma. Available from http://www.clinicaltrials.gov [Accessed 3 September 2009]