Biological function and inhibitors of mTOR: Research advances

Journal of International Pharmaceutical Research

Volumn 41, Issue 1, 2014, Pages 6-20

  Cao, Shuang ^a   Zhong, Wu ^a  

^a BEIJING INSTITUTE OF MICROBIOLOGY AND EPIDEMIOLOGY   (China)

Author keywords

Inhibitor; Mammalian target of sirolimus(mTOR); Signaling pathway; Sirolimus

Indexed keywords

ADENOSINE TRIPHOSPHATE DERIVATIVE; BINDING PROTEIN; FKBP12 PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; SIROLIMUS DERIVATIVE; UNCLASSIFIED DRUG;

AGING; ANTINEOPLASTIC ACTIVITY; ARTICLE; BIOLOGICAL ACTIVITY; CELL CYCLE REGULATION; CELL DIFFERENTIATION; CELL GROWTH; G1 PHASE CELL CYCLE CHECKPOINT; IMMUNOSUPPRESSIVE TREATMENT; SIGNAL TRANSDUCTION;

EID: 84906819342     PISSN: 16740440     EISSN: None     Source Type: Journal    
DOI: 10.13220/j.cnki.jipr.2014.01.002     Document Type: Article

References (66)

1. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant Rapamycin in yeast[J]. Science, 1991, 253(5022):905-909.
2. Verheijen JC, Nowak P, Cole DC, et al. Discovery of potent and selective inhibitors of the mammalian target of Rapamycin (mTOR) Kinase[J]. J Med Chem, 2009, 52(22):7081-7089.
3. Yang H, Rudge DG, Koos JD, et al. mTOR Kinase structure, mechanism and regulation[J]. Nature, 2013, 497(7448):217-223.
4. Hay N, Sonenberg N. Upstream and downstream of mTOR[J]. Gene Dev, 2004, 18(16):1926-1945.
5. Laplante M, Sabatini DM. mTOR Signaling in growth control and disease[J]. Cell, 2012, 149(2):274-293.
6. Gomez-Pinillos A, Ferrari AC. mTOR Signaling pathway and mTOR inhibitors in cancer therapy[J]. Hematol Oncol Clin North Am, 2012, 26(3):483-505.
7. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling[J]. Nat Cell Biol, 2002, 4(9):648-657.
8. Manning BD, Tee AR, Logsdon MN, et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway[J]. Mol Cell, 2002, 10(1):151-162.
9. Potter CJ, Pedraza LG, Xu T. Akt Regulates growth by directly phosphorylating TSC2[J]. Nat Cell Biol, 2002, 4(9):658-665.
10. 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[J]. Mol Cell, 2003, 11(6):1457-1466.
11. Inoki K, Ouyang H, Zhu T, et al. TSC2 Integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth[J]. Cell, 2006, 126(5):955-968.
12. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression[J]. Nat Rev Cancer, 2009, 9(8):563-575.
13. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model[J]. J Clin Invest, 2008, 118(9):3051-3064.
14. Yu CF, Liu ZX, Cantley LG. ERK Negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase[J]. J Biol Chem, 2002, 277(22):19382-19388.
15. Ma L, Chen Z, Erdjument-Bromage H, et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis[J]. Cell, 2005, 121(2):179-193.
16. Zinzalla V, Stracka D, Oppliger W, et al. Activation of mTORC2 by association with the ribosome[J]. Cell, 2011, 144(5):757-768.
17. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB[J]. Mol Cell, 2006, 22(2):159-168.
18. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control[J]. Nat Rev Mol Cell Biol, 2009, 10(5):307-318.
19. Ali SM, Sabatini DM. Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site[J]. J Biol Chem, 2005, 280(20):19445-19448.
20. Tang H, Hornstein E, Stolovich M, et al. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by Rapamycin, and is independent of S6K1 and rpS6 phosphorylation[J]. Mol Cell Biol, 2001, 21(24):8671-8683.
21. Yang S, Xiao X, Meng X, et al. A mechanism for synergy with combined mTOR and PI3 kinase inhibitors[J]. PLoS One, 2011, 6(10):e26343.
22. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy[J]. Oncogene, 2008, 27(41):5477-5485.
23. Shackelford DB, Vasquez DS, Corbeil J, et al. mTOR And HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome[J]. Proc Natl Acad Sci USA, 2009, 106(27):11137-11142.
24. Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition[J]. Am J Kidney Dis, 2012, 59(2):276-283.
25. Mavrakis KJ, Zhu H, Silva RL, et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase[J]. Gene Dev, 2008, 22(16):2178-2188.
26. 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]. J Clin Oncol, 2004, 22(5):909-918.
27. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy[J]. J Clin Invest, 2011, 121(4):1231-1241.
28. Nelson V, Altman JK, Platanias LC. Next generation of mammalian target of Rapamycin inhibitors for the treatment of cancer[J]. Expert Opin Inv Drugs, 2013, 22(6):715-722.
29. Hayakawa M, Kaizawa H, Moritomo H, et al. Synthesis and biological evaluation of pyrido[3', 2':4, 5]furo[3, 2-d]pyrimidine derivatives as novel PI3 kinase p110 alpha inhibitors[J]. Bioorg Med Chem Lett, 2007, 17(9):2438-2442.
30. Raynaud FI, Eccles S, Clarke PA, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases[J]. Cancer Res, 2007, 67(12):5840-5850.
31. Verheijen JC, Richard DJ, Curran K, et al. 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]. J Med Chem, 2009, 52(24):8010-8024.
32. Verheijen JC, Zask A, Verheijen JC, et al. ATP-Competitive inhibitors of the mammalian target of Rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines[J]. J Med Chem, 2009, 52(16):5013-5016.
33. 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[J]. Cancer Res, 2009, 69(15):6232-40.
34. Lv X, Ma X, Hu Y. Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment[J]. Expert Opin Drug Discov, 2013, 8(8):991-1012.
35. Folkes AJ, Ahmadi K, Alderton WK, et al. 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]. J Med Chem, 2008, 51(18):5522-5532.
36. Raynaud FI, Eccles SA, Patel S, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941[J]. Mol Cancer Ther, 2009, 8(7):1725-1738.
37. Heffron TP, Berry M, Castanedo G, et al. Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor[J]. Bioorg Med Chem Lett, 2010, 20(8):2408-2411.
38. Sutherlin DP, Bao L, Berry M, et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of Rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer[J]. J Med Chem, 2011, 54(21):7579-7587.
39. Wallin JJ, Edgar KA, Guan J, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway[J]. Mol Cancer Ther, 2011, 10(12):2426-36.
40. Verheijen JC, Dehnhardt CM, Venkatesan AM, et al. Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of Rapamycin inhibitors: discovery of PKI-402[J]. J Med Chem, 2010, 53(2):798-810.
41. Verheijen JC, Kaplan J, Brooijmans N, et al. 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)[J]. Bioorg Med Chem Lett, 2010, 20(2):640-643.
42. Verheijen JC, Venkatesan AM, Dehnhardt CM, 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]. J Med Chem, 2010, 53(6):2636-2645.
43. Venkatesan AM, Chen Z, dos Santos O, et al. PKI-179:An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor[J]. Bioorg Med Chem Lett, 2010, 20(19):5869-5873.
44. Cohen F, Bergeron P, Blackwood E, et al. Potent, selective, and orally bioavailable inhibitors of mammalian target of Rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine[J]. J Med Chem, 2011, 54(9):3426-3435.
45. Verheijen JC, Richard DJ, Curran K, et al. 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[J]. Bioorg Med Chem Lett, 2010, 20(8):2648-2653.
46. Liu KK, Bailey S, Dinh DM, et al. Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(15):5114-5117.
47. Cohen F, Bergeron P, Blackwood E, et al. Potent, selective, and orally bioavailable inhibitors of mammalian target of Rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine[J]. J Med Chem, 2011, 54(9):3426-3435.
48. Koehler MF, Bergeron P, Blackwood E, et al. Potent, selective, and orally bioavailable inhibitors of the mammalian target of Rapamycin kinase domain exhibiting single agent antiproliferative activity[J]. J Med Chem, 2012, 55(24):10958-10971.
49. D'Angelo ND, Kim TS, Andrews K, et al. Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of Rapamycin (mTOR) dual inhibitors[J]. J Med Chem, 2011, 54(6):1789-1811.
50. Nishimura N, Siegmund A, Liu L, et al. Phospshoinositide 3-kinase (PI3K)/mammalian target of Rapamycin (mTOR) dual inhibitors: discovery and structure activity relationships of a series of quinoline and quinoxaline derivatives[J]. J Med Chem, 2011, 54(13):4735-4751.
51. Leung E, Kim JE, Rewcastle GW, et al. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK-2126458 on tamoxifen-resistant breast cancer cells[J]. Cancer Biol Ther, 2011, 11(11):938-946.
52. Stauffer F, Maira SM, Furet P, et al. Imidazo[4, 5-c]quinolines as inhibitors of the PI3K/PKB-pathway[J]. Bioorg Med Chem Lett, 2008, 18(3):1027-1030.
53. 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[J]. Mol Cancer Ther, 2008, 7(7):1851-1863.
54. 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[J]. Cancer Res, 2008, 68(19):8022-8030.
55. Baumann P, Schneider L, Mandl-Weber S, et al. Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma[J]. Anti-Cancer Drugs, 2012, 23(1):131-138.
56. Chang KY, Tsai SY, Wu CM, et al. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo[J]. Clin Cancer Res, 2011, 17(22):7116-7126.
57. Liu Q, Chang JW, Wang J, et al. Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1, 6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of Rapamycin (mTOR) inhibitor for the treatment of cancer[J]. J Med Chem, 2010, 53(19):7146-7155.
58. Liu Q, Wang J, Kang SA, et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1, 6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of Rapamycin (mTOR) inhibitor for treatment of cancer[J]. J Med Chem, 2011, 54(5):1473-1480.
59. Yuan J, Mehta PP, Yin MJ, et al. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity[J]. Mol Cancer Ther, 2011, 10(11):2189-2199.
60. Liu KK, Bagrodia S, Bailey S, et al. 4-Methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors[J]. Bioorg Med Chem Lett, 2010, 20(20):6096-6099.
61. Le PT, Cheng H, Ninkovic S, et al. Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kalpha and mTOR[J]. Bioorg Med Chem Lett, 2012, 22(15):5098-5103.
62. Cheng H, Hoffman JE, Le PT, et al. Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series[J]. Bioorg Med Chem Lett, 2013, 23(9):2787-2792.
63. Apsel B, Blair JA, Gonzalez B, et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases[J]. Nat Chem Biol, 2008, 4(11):691-699.
64. Guo Y, Kwiatkowski DJ. Equivalent benefit of Rapamycin and a potent mTOR ATP-competitive inhibitor, MLN0128 (INK128), in a mouse model of tuberous sclerosis[J]. Mol Cancer Res, 2013, 11(5):467-473.
65. Buchanan SG, Hendle J, Lee PS, et al. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo[J]. Mol Cancer Ther, 2009, 8(12):3181-3190.
66. Nacht M, Qiao L, Sheets MP, et al. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3K alpha[J]. J Med Chem, 2013, 56(3):712-721