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Phosphoinositide 3-kinase in Health and Disease pp 241–262Cite as

New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitors (TORKinibs)

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 347))

Abstract

mTOR (mammalian Target of Rapamycin) is the hub of the phosphoinositide 3-Kinase (PI3-K)→Akt→mTOR pathway, which is one of the most commonly mutated pathways in cancer. PI3-Ks and mTOR are related kinases which share an evolutionarily related kinase domain, although the former is a lipid kinase and the latter is a protein kinase. As a result of their similar ATP sites, the prototypical PI3-K inhibitors LY294002 and wortmannin inhibit both kinases, although the compounds have been primarily thought of as inhibitors of PI3-Ks. The widespread use of these reagents to understand PI3-K signaling and the likelihood that many of their effects are confounded by dual inhibition of PI3-K and mTOR make it essential to develop selective mTOR inhibitors in part to understand the unique cellular effects of inhibition of this key downstream component in the growth factor pathway. Rapamycin has historically provided a means for selective mTOR inhibition, yet it is not a typical ATP competitive inhibitor, making its effects difficult to reconcile with LY294002 and wortmannin. Several groups have recently reported pharmacological agents which inhibit mTOR but not PI3-K, providing a new pharmacological approach to selective mTOR inhibition. The TOR kinase domain inhibitors of mTOR have been termed TORKinibs to distinguish their mode of action from rapamycin and its analogs (rapalogs). These inhibitors bind to the ATP binding site of the kinase domain of mTOR and as a result inhibit both mTOR complexes, TORC1 (rapamycin sensitive) and TORC2 (rapamycin resistant). These molecules have allowed a reinvestigation of mTOR and in particular a reinvestigation of the mechanistic basis for incomplete proliferative arrest of cells by Rapamycin. A consensus has quickly emerged from the study of various TORKinibs that Rapamycin is ineffective at blocking cell proliferation because it only partially inhibits the activity of mTORC1. The profound anti-proliferative effect of TORKinibs suggests that as the molecules enter the clinic they may be successful in the treatment of cancers where rapamycin has failed.

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References

  • Abraham RT, Wiederrecht GJ (1996) Immunopharmacology of rapamycin. Annu Rev Immunol 14:483–510

    Article  PubMed  CAS  Google Scholar 

  • Andjelkovic M et al (1997) Role of translocation in the activation and function of protein kinase B. J Biol Chem 272(50):31515–31524

    Article  PubMed  CAS  Google Scholar 

  • Apsel B et al (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol 4(11):691–699

    Article  PubMed  CAS  Google Scholar 

  • Brown EJ et al (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369(6483):756–758

    Article  PubMed  CAS  Google Scholar 

  • Brunn GJ et al (1996) Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. Embo J 15(19):5256–5267

    PubMed  CAS  Google Scholar 

  • Brunn GJ et al (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277(5322):99–101

    Article  PubMed  CAS  Google Scholar 

  • Burnett PE et al (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95(4):1432–1437

    Article  PubMed  CAS  Google Scholar 

  • Cafferkey R et al (1993) Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol Cell Biol 13(10):6012–6023

    PubMed  CAS  Google Scholar 

  • Carracedo A et al (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118(9):3065–3074

    PubMed  CAS  Google Scholar 

  • Chan TO, Tsichlis PN (2001) PDK2: a complex tail in one Akt. Sci STKE 2001(66):PE1

    Article  PubMed  CAS  Google Scholar 

  • Chen Y et al (1994) A putative sirolimus (rapamycin) effector protein. Biochem Biophys Res Commun 203(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Chiu MI, Katz H, Berlin V (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 91(26):12574–12578

    Article  PubMed  CAS  Google Scholar 

  • Chresta CM et al (2010) AZD8055 is a potent, selective and orally bioavailable ATP-Competitive mTOR kinase inhibitor with in vitro and in vivo anti-tumor activity. Cancer Res 70(1):288–298

    Article  Google Scholar 

  • Collins BJ et al (2003) In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. Embo J 22(16):4202–4211

    Article  PubMed  CAS  Google Scholar 

  • Facchinetti V et al (2008) The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. Embo J 27(14):1932–1943

    Article  PubMed  CAS  Google Scholar 

  • Fan QW et al (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9(5):341–349

    Article  PubMed  CAS  Google Scholar 

  • Fang Y et al (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294(5548):1942–1945

    Article  PubMed  CAS  Google Scholar 

  • Feldman ME et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38

    Article  PubMed  Google Scholar 

  • Folkes AJ et al (2008) 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 51(18):5522–5532

    Article  PubMed  CAS  Google Scholar 

  • Foster DA (2007) Regulation of mTOR by phosphatidic acid? Cancer Res 67(1):1–4

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Martinez JM, Alessi DR (2008) mTOR complex-2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoid induced protein kinase-1 (SGK1). Biochem J 416(3):375–385

    Article  Google Scholar 

  • Garcia-Martinez JM et al (2009) Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 421(1):29–42

    Article  PubMed  CAS  Google Scholar 

  • Gingras AC et al (1999) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 13(11):1422–1437

    Article  PubMed  CAS  Google Scholar 

  • Gingras AC et al (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15(21):2852–2864

    PubMed  CAS  Google Scholar 

  • Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22

    Article  PubMed  CAS  Google Scholar 

  • Guertin DA et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871

    Article  PubMed  CAS  Google Scholar 

  • Guertin DA et al (2009) mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15(2):148–159

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  • Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253(5022):905–909

    Article  PubMed  CAS  Google Scholar 

  • Helliwell SB et al (1994) TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell 5(1):105–118

    PubMed  CAS  Google Scholar 

  • Hresko RC, Mueckler M (2005) mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280(49):40406–40416

    Article  PubMed  CAS  Google Scholar 

  • Ikenoue T et al (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. Embo J 27(14):1919–1931

    Article  PubMed  CAS  Google Scholar 

  • Inoki K, Guan KL (2009) Tuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment. Hum Mol Genet 18(R1):R94–100

    Article  PubMed  CAS  Google Scholar 

  • Jacinto E, Lorberg A (2008) TOR regulation of AGC kinases in yeast and mammals. Biochem J 410(1):19–37

    Article  PubMed  CAS  Google Scholar 

  • Jacinto E et al (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137

    Article  PubMed  CAS  Google Scholar 

  • Kannan N et al (2007) The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Proc Natl Acad Sci USA 104(4):1272–1277

    Article  PubMed  CAS  Google Scholar 

  • Kim DH et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175

    Article  PubMed  CAS  Google Scholar 

  • Kinkade CW et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118(9):3051–3064

    PubMed  CAS  Google Scholar 

  • Knight ZA, Shokat KM (2005) Features of selective kinase inhibitors. Chem Biol 12(6):621–637

    Article  PubMed  CAS  Google Scholar 

  • Knight ZA et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125(4):733–747

    Article  PubMed  CAS  Google Scholar 

  • Kumar A et al (2008) Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol Cell Biol 28(1):61–70

    Article  PubMed  CAS  Google Scholar 

  • Kunz J et al (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596

    Article  PubMed  CAS  Google Scholar 

  • Li J et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    Article  PubMed  CAS  Google Scholar 

  • Loewith R et al (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10(3):457–468

    Article  PubMed  CAS  Google Scholar 

  • Maira SM et al (2008) 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 7(7):1851–1863

    Article  PubMed  CAS  Google Scholar 

  • Manning BD et al (2005) Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 19(15):1773–1778

    Article  PubMed  CAS  Google Scholar 

  • Nowak P et al (2009) Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase. J Med Chem 52(22):7081–7089

    Article  Google Scholar 

  • Okuzumi T et al (2009) Inhibitor hijacking of Akt activation. Nat Chem Biol 5(7):484–493

    Article  PubMed  CAS  Google Scholar 

  • Pearson RB et al (1995) The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. Embo J 14(21):5279–5287

    PubMed  CAS  Google Scholar 

  • Raynaud FI et al (2009) 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. Mol Cancer Ther 8(7):1725–1738

    Article  PubMed  CAS  Google Scholar 

  • Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433(7025):477–480

    Article  PubMed  CAS  Google Scholar 

  • Rini B, Kar S, Kirkpatrick P (2007) Temsirolimus. Nat Rev Drug Discov 6(8):599–600

    Article  CAS  Google Scholar 

  • Ruggero D, Pandolfi PP (2003) Does the ribosome translate cancer? Nat Rev Cancer 3(3):179–92

    Article  PubMed  CAS  Google Scholar 

  • Ruggero D, Sonenberg N (2005) The Akt of translational control. Oncogene 24(50):7426–7434

    Article  PubMed  CAS  Google Scholar 

  • Ruggero D et al (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10(5):484–486

    Article  PubMed  CAS  Google Scholar 

  • Sabatini DM et al (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78(1):35–43

    Article  PubMed  CAS  Google Scholar 

  • Sabers CJ et al (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270(2):815–822

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168

    Article  PubMed  CAS  Google Scholar 

  • Sedrani R et al (1998) Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc 30(5):2192–2194

    Article  PubMed  CAS  Google Scholar 

  • Shiota C et al (2006) Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 11(4):583–589

    Article  PubMed  CAS  Google Scholar 

  • Shor B et al (2008) A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 68(8):2934–2943

    Article  PubMed  CAS  Google Scholar 

  • Sonenberg N, Hershey JWB, Mathews M (2000) Translational control of gene expression, 2nd edn. Cold Spring Harbor monograph series, vol 39. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 1020

    Google Scholar 

  • Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7(2):85–96

    Article  PubMed  CAS  Google Scholar 

  • Thoreen CC et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032

    Article  PubMed  CAS  Google Scholar 

  • Veverka V et al (2008) Structural characterization of the interaction of mTOR with phosphatidic acid and a novel class of inhibitor: compelling evidence for a central role of the FRB domain in small molecule-mediated regulation of mTOR. Oncogene 27(5):585–595

    Article  PubMed  CAS  Google Scholar 

  • Vlahos CJ et al (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269(7):5241–5248

    PubMed  CAS  Google Scholar 

  • Walker EH et al (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6(4):909–919

    Article  PubMed  CAS  Google Scholar 

  • Wan X et al (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940

    Article  PubMed  CAS  Google Scholar 

  • Wang X et al (2005) Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol 25(7):2558–2572

    Article  PubMed  CAS  Google Scholar 

  • Yang J et al (2002) Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol 9(12):940–944

    Article  PubMed  CAS  Google Scholar 

  • Yu K et al (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69(15):6232–6240

    Article  PubMed  CAS  Google Scholar 

  • Zask A et al 2009 ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. J Med Chem 52(16):5013–5016

    Article  PubMed  CAS  Google Scholar 

  • Zheng XF et al (1995) TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82(1):121–130

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, UC San Francisco, 600 16th St., Genentech Hall, San Francisco, CA, 94158, USA

    Morris E. Feldman & Kevan M. Shokat

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  1. Morris E. Feldman
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  2. Kevan M. Shokat
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Correspondence to Kevan M. Shokat .

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  1. Intellikine, North Torreye Pines Road 10931, La Jolla, 92037, California, USA

    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

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Feldman, M.E., Shokat, K.M. (2010). New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitors (TORKinibs). In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 347. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_64

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