Research Progress of 70 kDa Ribosomal Protein S6 Kinase (P70S6K) Inhibitors as Effective Therapeutic Tools for Obesity, Type II Diabetes and Cancer

Author(s): Na Zhang, Shutao Ma*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 28 , 2020

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At present, diseases such as obesity, type Ⅱ diabetes and cancer have brought serious health problems, which are closely related to mTOR pathway. 70 kDa ribosomal protein S6 kinase (p70S6K), as a significant downstream effector of mTOR, mediates protein synthesis, RNA processing, glucose homeostasis, cell growth and apoptosis. Inhibiting the function of p70S6K can reduce the risk of obesity which helps to treat dyslipidemia, enhance insulin sensitivity, and extend the life span of mammals. Therefore, p70S6K has become a potential target for the treatment of these diseases. So far, except for the first p70S6K specific inhibitor PF-4708671 developed by Pfizer and LY2584702 developed by Lilai, all of them are in preclinical research. This paper briefly introduces the general situation of p70S6K and reviews their inhibitors in recent years, which are mainly classified into two categories: natural compounds and synthetic compounds. In particular, their inhibitory activities, structure-activity relationships (SARs) and mechanisms are highlighted.

Keywords: p70S6K, potential target, diseases, inhibitors, activity, structure-activity relationships.

Peterson, R.T.; Schreiber, S.L. Kinase phosphorylation: Keeping it all in the family. Curr. Biol., 1999, 9(14), R521-R524.
[] [PMID: 10421571]
Ziegler, W.H.; Parekh, D.B.; Le Good, J.A.; Whelan, R.D.H.; Kelly, J.J.; Frech, M.; Hemmings, B.A.; Parker, P.J. Rapamycin sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex. Curr. Biol., 1999, 9(10), 522-529.
[] [PMID: 10339425]
Brazil, D.P.; Hemmings, B.A. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci., 2001, 26(11), 657-664.
[] [PMID: 11701324]
Coffer, P.J.; Woodgett, J.R. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur. J. Biochem., 1991, 201(2), 475-481.
[] [PMID: 1718748]
Grove, J.R.; Banerjee, P.; Balasubramanyam, A.; Coffer, P.J.; Price, D.J.; Avruch, J.; Woodgett, J.R. Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini. Mol. Cell. Biol., 1991, 11(11), 5541-5550.
[] [PMID: 1922062]
Gout, I.; Minami, T.; Hara, K.; Tsujishita, Y.; Filonenko, V.; Waterfield, M.D.; Yonezawa, K. Molecular cloning and characterization of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich region. J. Biol. Chem., 1998, 273(46), 30061-30064.
[] [PMID: 9804755]
Proud, C.G. Regulation of mammalian translation factors by nutrients. Eur. J. Biochem., 2002, 269(22), 5338-5349.
[] [PMID: 12423332]
Schmelzle, T.; Hall, M.N. TOR, a central controller of cell growth. Cell, 2000, 103(2), 253-262.
[] [PMID: 11057898]
Gassaway, B.M.; Petersen, M.C.; Surovtseva, Y.V.; Barber, K.W.; Sheetz, J.B.; Aerni, H.R.; Merkel, J.S.; Samuel, V.T.; Shulman, G.I.; Rinehart, J. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proc. Natl. Acad. Sci. USA, 2018, 115(38), E8996-E9005.
[] [PMID: 30181290]
Csibi, A.; Lee, G.; Yoon, S-O.; Tong, H.; Ilter, D.; Elia, I.; Fendt, S-M.; Roberts, T.M.; Blenis, J. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr. Biol., 2014, 24(19), 2274-2280.
[] [PMID: 25220053]
Wang, X.; Li, W.; Williams, M.; Terada, N.; Alessi, D.R.; Proud, C.G. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J., 2001, 20(16), 4370-4379.
[] [PMID: 11500364]
Harada, H.; Andersen, J.S.; Mann, M.; Terada, N.; Korsmeyer, S.J. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc. Natl. Acad. Sci. USA, 2001, 98(17), 9666-9670.
[] [PMID: 11493700]
Bailey, J.; Tyson-Capper, A.J.; Gilmore, K.; Robson, S.C.; Europe-Finner, G.N. Identification of human myometrial target genes of the cAMP pathway: the role of cAMP-response element binding (CREB) and modulator (CREMalpha and CREMtau2alpha) proteins. J. Mol. Endocrinol., 2005, 34(1), 1-17.
[] [PMID: 15691874]
Ruvinsky, I.; Meyuhas, O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem. Sci., 2006, 31(6), 342-348.
[] [PMID: 16679021]
Um, S.H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.; Sticker, M.; Fumagalli, S.; Allegrini, P.R.; Kozma, S.C.; Auwerx, J.; Thomas, G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature, 2004, 431(7007), 485-485.
Berven, L.A.; Willard, F.S.; Crouch, M.F. Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp. Cell Res., 2004, 296(2), 183-195.
[] [PMID: 15149849]
Weng, Q.P.; Andrabi, K.; Kozlowski, M.T.; Grove, J.R.; Avruch, J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol. Cell. Biol., 1995, 15(5), 2333-2340.
[] [PMID: 7739516]
Cheatham, L.; Monfar, M.; Chou, M.M.; Blenis, J. Structural and functional analysis of pp70S6k. Proc. Natl. Acad. Sci. USA, 1995, 92(25), 11696-11700.
[] [PMID: 8524831]
Dennis, P.B.; Pullen, N.; Kozma, S.C.; Thomas, G. The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol. Cell. Biol., 1996, 16(11), 6242-6251.
[] [PMID: 8887654]
Pearson, R.B.; Dennis, P.B.; Han, J.W.; Williamson, N.A.; Kozma, S.C.; Wettenhall, R.E.H.; Thomas, G. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J., 1995, 14(21), 5279-5287.
[] [PMID: 7489717]
Weng, Q.P.; Andrabi, K.; Klippel, A.; Kozlowski, M.T.; Williams, L.T.; Avruch, J. Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site specific p70 phosphorylation. Proc. Natl. Acad. Sci. USA, 1995, 92(12), 5744-5748.
[] [PMID: 7777579]
Kannan, N.; Haste, N.; Taylor, S.S.; Neuwald, A.F. The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Proc. Natl. Acad. Sci. USA, 2007, 104(4), 1272-1277.
[] [PMID: 17227859]
Ferrari, S.; Bannwarth, W.; Morley, S.J.; Totty, N.F.; Thomas, G. Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs. Proc. Natl. Acad. Sci. USA, 1992, 89(15), 7282-7286.
[] [PMID: 1496022]
Hauge, C.; Antal, T.L.; Hirschberg, D.; Doehn, U.; Thorup, K.; Idrissova, L.; Hansen, K.; Jensen, O.N.; Jørgensen, T.J.; Biondi, R.M.; Frödin, M. Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. EMBO J., 2007, 26(9), 2251-2261.
[] [PMID: 17446865]
Keshwani, M.M.; von Daake, S.; Newton, A.C.; Harris, T.K.; Taylor, S.S. Hydrophobic motif phosphorylation is not required for activation loop phosphorylation of p70 ribosomal protein S6 kinase 1 (S6K1). J. Biol. Chem., 2011, 286(26), 23552-23558.
[] [PMID: 21561857]
Keranen, L.M.; Dutil, E.M.; Newton, A.C. Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr. Biol., 1995, 5(12), 1394-1403.
[] [PMID: 8749392]
Bandarage, U.; Hare, B.; Parsons, J.; Pham, L.; Marhefka, C.; Bemis, G.; Tang, Q.; Moody, C.S.; Rodems, S.; Shah, S.; Adams, C.; Bravo, J.; Charonnet, E.; Savic, V.; Come, J.H.; Green, J. 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(17), 5191-5194.
[] [PMID: 19632115]
Wenlei, B.; Xiyan, H.; Xu, Z.; Yan, L.; Yuhao, C.; Yanfeng, W.; Zhigang, W. Molecular Characterization and Expression Analysis of Ribosomal Protein S6 Gene in the Cashmere Goat (Capra hircus). Asian-Australas. J. Anim. Sci., 2013, 26(11), 1644-1650.
[] [PMID: 25049753]
Raught, B.; Peiretti, F.; Gingras, A.C.; Livingstone, M.; Shahbazian, D.; Mayeur, G.L.; Polakiewicz, R.D.; Sonenberg, N.; Hershey, J.W.B. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J., 2004, 23(8), 1761-1769.
[] [PMID: 15071500]
Montero, H.; Pérez-Gil, G.; Sampieri, C.L. Eukaryotic initiation factor 4A (eIF4A) during viral infections. Virus Genes, 2019, 55(3), 267-273.
[] [PMID: 30796742]
Matsuhashi, S.; Manirujjaman, M.; Hamajima, H.; Ozaki, I. Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions. Int. J. Mol. Sci., 2019, 20(9) E2304
[] [PMID: 31075975]
Wang, B.; Li, Y. Evidence for the direct involvement of βTrCP in Gli3 protein processing. Proc. Natl. Acad. Sci. USA, 2006, 103(1), 33-38.
[] [PMID: 16371461]
Dorrello, N.V.; Peschiaroli, A.; Guardavaccaro, D.; Colburn, N.H.; Sherman, N.E.; Pagano, M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science, 2006, 314(5798), 467-471.
[] [PMID: 17053147]
Bian, C-X.; Shi, Z.; Meng, Q.; Jiang, Y.; Liu, L-Z.; Jiang, B-H. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression. Biochem. Biophys. Res. Commun., 2010, 398(3), 395-399.
[] [PMID: 20599538]
Skinner, H.D.; Zheng, J.Z.; Fang, J.; Agani, F.; Jiang, B.H. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1alpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J. Biol. Chem., 2004, 279(44), 45643-45651.
[] [PMID: 15337760]
Ben-Hur, V.; Denichenko, P.; Siegfried, Z.; Maimon, A.; Krainer, A.; Davidson, B.; Karni, R. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep., 2013, 3(1), 103-115.
[] [PMID: 23273915]
Heitman, J.; Movva, N.R.; Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 1991, 253(5022), 905-909.
[] [PMID: 1715094]
Jiang, K.; Chen, H.; Tang, K.; Guan, W.; Zhou, H.; Guo, X.; Chen, Z.; Ye, Z.; Xu, H. Puerarin inhibits bladder cancer cell proliferation through the mTOR/p70S6K signaling pathway. Oncol. Lett., 2018, 15(1), 167-174.
[PMID: 29375709]
Rosa, R.; Damiano, V.; Nappi, L.; Formisano, L.; Massari, F.; Scarpa, A.; Martignoni, G.; Bianco, R.; Tortora, G. Angiogenic and signalling proteins correlate with sensitivity to sequential treatment in renal cell cancer. Br. J. Cancer, 2013, 109(3), 686-693.
[] [PMID: 23839492]
Li, S-H.; Chen, C-H.; Lu, H-I.; Huang, W-T.; Tien, W-Y.; Lan, Y-C.; Lee, C-C.; Chen, Y-H.; Huang, H-Y.; Chang, A.Y.W.; Lin, W-C. Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma. Surgery, 2015, 157(3), 570-580.
[] [PMID: 25726316]
Maruani, D.M.; Spiegel, T.N.; Harris, E.N.; Shachter, A.S.; Unger, H.A.; Herrero-González, S.; Holz, M.K. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene, 2012, 31(49), 5073-5080.
[] [PMID: 22286763]
Pérez-Tenorio, G.; Karlsson, E.; Waltersson, M.A.; Olsson, B.; Holmlund, B.; Nordenskjöld, B.; Fornander, T.; Skoog, L.; Stål, O. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res. Treat., 2011, 128(3), 713-723.
[] [PMID: 20953835]
Holz, M.K. The role of S6K1 in ER-positive breast cancer. Cell Cycle, 2012, 11(17), 3159-3165.
[] [PMID: 22895181]
Longo, M.; Zatterale, F.; Naderi, J.; Parrillo, L.; Formisano, P.; Raciti, G.A.; Beguinot, F.; Miele, C. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int. J. Mol. Sci., 2019, 20(9) E2358
[] [PMID: 31085992]
McLaughlin, T.; Craig, C.; Liu, L-F.; Perelman, D.; Allister, C.; Spielman, D.; Cushman, S.W. Adipose cell size and regional fat deposition as predictors of metabolic response to overfeeding in insulin-resistant and insulin-sensitive humans. Diabetes, 2016, 65(5), 1245-1254.
[] [PMID: 26884438]
Birsoy, K.; Festuccia, W.T.; Laplante, M. A comparative perspective on lipid storage in animals. J. Cell Sci., 2013, 126(Pt 7), 1541-1552.
[] [PMID: 23658371]
Um, S.H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.; Sticker, M.; Fumagalli, S.; Allegrini, P.R.; Kozma, S.C.; Auwerx, J.; Thomas, G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature, 2004, 431(7005), 200-205.
[] [PMID: 15306821]
Tzatsos, A.; Kandror, K.V. 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.
[] [PMID: 16354680]
Chung, J.; Grammer, T.C.; Lemon, K.P.; Kazlauskas, A.; Blenis, J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature, 1994, 370(6484), 71-75.
[] [PMID: 8015612]
Cross, D.A.E.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995, 378(6559), 785-789.
[] [PMID: 8524413]
Harrington, L.S.; Findlay, G.M.; Gray, A.; Tolkacheva, T.; Wigfield, S.; Rebholz, H.; Barnett, J.; Leslie, N.R.; Cheng, S.; Shepherd, P.R.; Gout, I.; Downes, C.P.; Lamb, R.F. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol., 2004, 166(2), 213-223.
[] [PMID: 15249583]
Piedfer, M.; Bouchet, S.; Tang, R.; Billard, C.; Dauzonne, D.; Bauvois, B. p70S6 kinase is a target of the novel proteasome inhibitor 3,3′-diamino-4′-methoxyflavone during apoptosis in human myeloid tumor cells. Biochim. Biophys. Acta, 2013, 1833(6), 1316-1328.
[] [PMID: 23481040]
Arai, Y.; Watanabe, S.; Kimira, M.; Shimoi, K.; Mochizuki, R.; Kinae, N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J. Nutr., 2000, 130(9), 2243-2250.
[] [PMID: 10958819]
Syed, D.N.; Afaq, F.; Maddodi, N.; Johnson, J.J.; Sarfaraz, S.; Ahmad, A.; Setaluri, V.; Mukhtar, H. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels. J. Invest. Dermatol., 2011, 131(6), 1291-1299.
[] [PMID: 21346776]
Sechi, M.; Lall, R.K.; Afolabi, S.O.; Singh, A.; Joshi, D.C.; Chiu, S-Y.; Mukhtar, H.; Syed, D.N. Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models. Sci. Rep., 2018, 8(1), 15726.
[] [PMID: 30356079]
Syed, D.N.; Chamcheu, J-C.; Khan, M.I.; Sechi, M.; Lall, R.K.; Adhami, V.M.; Mukhtar, H. Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem. Pharmacol., 2014, 89(3), 349-360.
[] [PMID: 24675012]
Jang, M.; Cai, L.; Udeani, G.O.; Slowing, K.V.; Thomas, C.F.; Beecher, C.W.W.; Fong, H.H.S.; Farnsworth, N.R.; Kinghorn, A.D.; Mehta, R.G.; Moon, R.C.; Pezzuto, J.M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 1997, 275(5297), 218-220.
[] [PMID: 8985016]
Alkhalaf, M. Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology, 2007, 80(2-3), 134-143.
[] [PMID: 17534123]
Thiyagarajan, V.; Lee, K-W.; Leong, M.K.; Weng, C-F. Potential natural mTOR inhibitors screened by in silico approach and suppress hepatic stellate cells activation. J. Biomol. Struct. Dyn., 2018, 36(16), 4220-4234.
[] [PMID: 29183268]
Yu, C-C.; Chiang, P-C.; Lu, P-H.; Kuo, M-T.; Wen, W-C.; Chen, P.; Guh, J-H. Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells. J. Nutr. Biochem., 2012, 23(8), 900-907.
[] [PMID: 21840189]
Lee, M.S.; Cha, E.Y.; Sul, J.Y.; Song, I.S.; Kim, J.Y. Chrysophanic acid blocks proliferation of colon cancer cells by inhibiting EGFR/mTOR pathway. Phytother. Res., 2011, 25(6), 833-837.
[] [PMID: 21089180]
Zhang, B.; Huang, H.; Xie, J.; Xu, C.; Chen, M.; Wang, C.; Yang, A.; Yin, Q. Cucurmosin induces apoptosis of BxPC-3 human pancreatic cancer cells via inactivation of the EGFR signaling pathway. Oncol. Rep., 2012, 27(3), 891-897.
[PMID: 22139427]
Jeong, J-H.; Jeong, Y-J.; Cho, H-J.; Shin, J-M.; Kang, J-H.; Park, K-K.; Park, Y-Y.; Chung, I-K.; Chang, H-W.; Magae, J.; Kang, S-S.; Chang, Y-C. Ascochlorin inhibits growth factor-induced HIF-1α activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells. J. Cell. Biochem., 2012, 113(4), 1302-1313.
[] [PMID: 22109717]
Shin, J-M.; Jeong, Y-J.; Cho, H-J.; Magae, J.; Bae, Y-S.; Chang, Y-C. Suppression of c-Myc induces apoptosis via an AMPK/mTOR-dependent pathway by 4-O-methyl ascochlorin in leukemia cells (vol 21, pg 657, 2016). Apoptosis, 2016, 21(5), 669-670.
[] [PMID: 27030036]
Pearce, L.R.; Alton, G.R.; Richter, D.T.; Kath, J.C.; Lingardo, L.; Chapman, J.; Hwang, C.; Alessi, D.R. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem. J., 2010, 431(2), 245-255.
[] [PMID: 20704563]
Holz, M.K.; Blenis, J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem., 2005, 280(28), 26089-26093.
[] [PMID: 15905173]
Treins, C.; Warne, P.H.; Magnuson, M.A.; Pende, M.; Downward, J. Rictor is a novel target of p70 S6 kinase-1. Oncogene, 2010, 29(7), 1003-1016.
[] [PMID: 19935711]
Wang, J.; Zhong, C.; Wang, F.; Qu, F.; Ding, J. Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif. Biochem. J., 2013, 454(1), 39-47.
[] [PMID: 23731517]
Sunami, T.; Byrne, N.; Diehl, R.E.; Funabashi, K.; Hall, D.L.; Ikuta, M.; Patel, S.B.; Shipman, J.M.; Smith, R.F.; Takahashi, I.; Zugay-Murphy, J.; Iwasawa, Y.; Lumb, K.J.; Munshi, S.K.; Sharma, S. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. J. Biol. Chem., 2010, 285(7), 4587-4594.
[] [PMID: 19864428]
Qiu, Z-X.; Sun, R-F.; Mo, X-M.; Li, W-M. The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth. PLoS One, 2016, 11(1) e0147185
[] [PMID: 26771549]
Shum, M.; Bellmann, K.; St-Pierre, P.; Marette, A. Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice. Diabetologia, 2016, 59(3), 592-603.
[] [PMID: 26733005]
Shum, M.; Houde, V.P.; Bellemare, V.; Junges Moreira, R.; Bellmann, K.; St-Pierre, P.; Viollet, B.; Foretz, M.; Marette, A. Inhibition of mitochondrial complex 1 by the S6K1 inhibitor PF-4708671 partly contributes to its glucose metabolic effects in muscle and liver cells. J. Biol. Chem., 2019, 294(32), 12250-12260.
[] [PMID: 31243102]
Lee-Fruman, K.K.; Kuo, C.J.; Lippincott, J.; Terada, N.; Blenis, J. Characterization of S6K2, a novel kinase homologous to S6K1. Oncogene, 1999, 18(36), 5108-5114.
[] [PMID: 10490847]
Bradshaw, D.; Hill, C.H.; Nixon, J.S.; Wilkinson, S.E. Therapeutic potential of protein kinase C inhibitors. Agents Actions, 1993, 38(1-2), 135-147.
[] [PMID: 8480534]
Roberts, N.A.; Marber, M.S.; Avkiran, M. Specificity of action of bisindolylmaleimide protein kinase C inhibitors: do they inhibit the 70kDa ribosomal S6 kinase in cardiac myocytes? Biochem. Pharmacol., 2004, 68(10), 1923-1928.
[] [PMID: 15476663]
Alessi, D.R. The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase-1beta (Rsk-2) and p70 S6 kinase. FEBS Lett., 1997, 402(2-3), 121-123.
[] [PMID: 9037179]
Marmy-Conus, N.; Hannan, K.M.; Pearson, R.B. Ro 31-6045, the inactive analogue of the protein kinase C inhibitor Ro 31-8220, blocks in vivo activation of p70(s6k)/p85(s6k): implications for the analysis of S6K signalling. FEBS Lett., 2002, 519(1-3), 135-140.
[] [PMID: 12023032]
Davies, S.P.; Reddy, H.; Caivano, M.; Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J., 2000, 351(Pt 1), 95-105.
[] [PMID: 10998351]
Pinner, S.; Sahai, E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat. Cell Biol., 2008, 10(2), 127-137.
[] [PMID: 18204440]
Couty, S.; Westwood, I.M.; Kalusa, A.; Cano, C.; Travers, J.; Boxall, K.; Chow, C.L.; Burns, S.; Schmitt, J.; Pickard, L.; Barillari, C.; McAndrew, P.C.; Clarke, P.A.; Linardopoulos, S.; Griffin, R.J.; Aherne, G.W.; Raynaud, F.I.; Workman, P.; Jones, K.; van Montfort, R.L.M. The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. Oncotarget, 2013, 4(10), 1647-1661.
[] [PMID: 24072592]
Stavenger, R.A.; Cui, H.; Dowdell, S.E.; Franz, R.G.; Gaitanopoulos, D.E.; Goodman, K.B.; Hilfiker, M.A.; Ivy, R.L.; Leber, J.D.; Marino, J.P., Jr; Oh, H.J.; Viet, A.Q.; Xu, W.; Ye, G.; Zhang, D.; Zhao, Y.; Jolivette, L.J.; Head, M.S.; Semus, S.F.; Elkins, P.A.; Kirkpatrick, R.B.; Dul, E.; Khandekar, S.S.; Yi, T.; Jung, D.K.; Wright, L.L.; Smith, G.K.; Behm, D.J.; Doe, C.P.; Bentley, R.; Chen, Z.X.; Hu, E.; Lee, D. Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity. J. Med. Chem., 2007, 50(1), 2-5.
[] [PMID: 17201404]
Bussenius, J.; Anand, N.K.; Blazey, C.M.; Bowles, O.J.; Bannen, L.C.; Chan, D.S.M.; Chen, B.; Co, E.W.; Costanzo, S.; DeFina, S.C.; Dubenko, L.; Engst, S.; Franzini, M.; Huang, P.; Jammalamadaka, V.; Khoury, R.G.; Kim, M.H.; Klein, R.R.; Laird, D.; Le, D.T.; Mac, M.B.; Matthews, D.J.; Markby, D.; Miller, N.; Nuss, J.M.; Parks, J.J.; Tsang, T.H.; Tsuhako, A.L.; Wang, Y.; Xu, W.; Rice, K.D. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(6), 2283-2286.
[] [PMID: 22342124]
Tolcher, A.; Goldman, J.; Patnaik, A.; Papadopoulos, K.P.; Westwood, P.; Kelly, C.S.; Bumgardner, W.; Sams, L.; Geeganage, S.; Wang, T.; Capen, A.R.; Huang, J.; Joseph, S.; Miller, J.; Benhadji, K.A.; Brail, L.H.; Rosen, L.S. A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours. Eur. J. Cancer, 2014, 50(5), 867-875.
[] [PMID: 24440085]
Leohr, J.K.; Luffer-Atlas, D.; Luo, M.J.; DeBrota, D.J.; Green, C.; Mabry, T.E.; Suico, J.G. Serum Lipid and Protein Changes in Healthy Dyslipidemic Subjects Given a Selective Inhibitor of p70 S6 Kinase-1. J. Clin. Pharmacol., 2018, 58(4), 412-424.
[] [PMID: 29178617]
Hollebecque, A.; Houédé, N.; Cohen, E.E.W.; Massard, C.; Italiano, A.; Westwood, P.; Bumgardner, W.; Miller, J.; Brail, L.H.; Benhadji, K.A.; Soria, J.C. A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours. Eur. J. Cancer, 2014, 50(5), 876-884.
[] [PMID: 24456794]
Qin, J.; Rajaratnam, R.; Feng, L.; Salami, J.; Barber-Rotenberg, J.S.; Domsic, J.; Reyes-Uribe, P.; Liu, H.; Dang, W.; Berger, S.L.; Villanueva, J.; Meggers, E.; Marmorstein, R. Development of organometallic S6K1 inhibitors. J. Med. Chem., 2015, 58(1), 305-314.
[] [PMID: 25356520]
Bae, E.J.; Yang, Y.M.; Kim, J.W.; Kim, S.G. Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway. Hepatology, 2007, 46(3), 730-739.
[] [PMID: 17668885]
Shin, S.M.; Kim, S.G. Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. Mol. Pharmacol., 2009, 75(1), 242-253.
[] [PMID: 18945820]
Moore, W.R., Jr; Springman, E.; Michelotti, E. Preparation of heteroarylaryl ureas as inhibitors of protein kinases. WO2006062984A2. 2006.
Ye, P.; Kuhn, C.; Juan, M.; Sharma, R.; Connolly, B.; Alton, G.; Liu, H.; Stanton, R.; Kablaoui, N.M. Potent and selective thiophene urea-templated inhibitors of S6K. Bioorg. Med. Chem. Lett., 2011, 21(2), 849-852.
[] [PMID: 21185721]
Quastel, J.H.; Cantero, A. Inhibition of tumour growth by D-glucosamine. Nature, 1953, 171(4345), 252-254.
[] [PMID: 13036842]
Bekesi, J.G.; Molnar, Z.; Winzler, R.J. Inhibitory effect of d-glucosamine and other sugar analogs on the viability and transplantability of ascites tumor cells. Cancer Res., 1969, 29(2), 353-359.
[PMID: 5765417]
Bekesi, J.G.; Winzler, R.J. Inhibitory effects of D-glucosamine on the growth of Walker 256 carcinosarcoma and on protein, RNA, and DNA synthesis. Cancer Res., 1970, 30(12), 2905-2912.
[PMID: 5494575]
Friedman, S.J.; Skehan, P. Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine. Proc. Natl. Acad. Sci. USA, 1980, 77(2), 1172-1176.
[] [PMID: 6928667]
Oh, H-J.; Lee, J.S.; Song, D-K.; Shin, D-H.; Jang, B-C.; Suh, S-I.; Park, J-W.; Suh, M-H.; Baek, W-K. D-glucosamine inhibits proliferation of human cancer cells through inhibition of p70S6K. Biochem. Biophys. Res. Commun., 2007, 360(4), 840-845.
[] [PMID: 17624310]
Radimerski, T.; Montagne, J.; Rintelen, F.; Stocker, H.; van der Kaay, J.; Downes, C.P.; Hafen, E.; Thomas, G. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat. Cell Biol., 2002, 4(3), 251-255.
[] [PMID: 11862217]
Hornstein, E.; Tang, H.; Meyuhas, O. Mitogenic and nutritional signals are transduced into translational efficiency of TOP mRNAs. Cold Spring Harb. Symp. Quant. Biol., 2001, 66, 477-484.
[] [PMID: 12762050]

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Article Details

Year: 2020
Published on: 06 August, 2020
Page: [4699 - 4719]
Pages: 21
DOI: 10.2174/0929867327666200114113139
Price: $65

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