Ribosomal S6 kinase (RSK) modulators: a patent review

References

• Sturgill TW, Ray LB, Erikson E, et al. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature. 1988;334(6184):715–718.
   PubMed Web of Science ®Google Scholar
• Erikson E, Maller JL. A protein kinase from Xenopus eggs specific for ribosomal protein S6. Proc Natl Acad Sci USA. 1985;82(3):742–746.
   PubMed Web of Science ®Google Scholar
• Jones SW, Erikson E, Blenis J, et al. A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases. Proc Natl Acad Sci USA. 1988;85(10):3377–3381.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Roux PP, Shahbazian D, Vu H, et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282(19):14056–14064.
   PubMed Web of Science ®Google Scholar
• Pereira PM, Schneider A, Pannetier S, et al. Coffin-Lowry syndrome. Eur J Hum Genet: EJHG. 2010;18(6):627–633.
   PubMed Web of Science ®Google Scholar
• Facher JJ, Regier EJ, Jacobs GH, et al. Cardiomyopathy in Coffin-Lowry syndrome. Am J Med Genet A. 2004;128A(2):176–178.
   PubMed Web of Science ®Google Scholar
• Schneider A, Mehmood T, Pannetier S, et al. Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin-Lowry syndrome. J Neurochem. 2011;119(3):447–459.
   PubMed Web of Science ®Google Scholar
• Poirier R, Jacquot S, Vaillend C, et al. Deletion of the Coffin-Lowry syndrome gene RSK2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. Behav Genet. 2007;37(1):31–50.
   PubMed Web of Science ®Google Scholar
• Yang X, Matsuda K, Bialek P, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry syndrome. Cell. 2004;117(3):387–398.
   PubMed Web of Science ®Google Scholar
• Putz G, Bertolucci F, Raabe T, et al. The S6KII (RSK) gene of Drosophila melanogaster differentially affects an operant and a classical learning task. J Neurosci. 2004;24(44):9745–9751.
   PubMed Web of Science ®Google Scholar
• Dumont J, Umbhauer M, Rassinier P, et al. p90RSK is not involved in cytostatic factor arrest in mouse oocytes. J Cell Biol. 2005;169(2):227–231.
   PubMed Web of Science ®Google Scholar
• Zeniou M, Ding T, Trivier E, et al. Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet. 2002;11(23):2929–2940.
   PubMed Web of Science ®Google Scholar
• Romeo Y, Zhang X, Roux PP. Regulation and function of the RSK family of protein kinases. Biochem J. 2012;441(2):553–569.
   PubMed Web of Science ®Google Scholar
• Ohno S. Evolution by gene duplication. Berlin, New York: Springer-Verlag; 1970.
   Google Scholar
• Dehal P, Boore JL. Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol. 2005;3(10):e314.
   PubMed Web of Science ®Google Scholar
• Fisher TL, Blenis J. Evidence for two catalytically active kinase domains in pp90RSK. Mol Cell Biol. 1996;16(3):1212–1219.
   PubMed Web of Science ®Google Scholar
• Dummler BA, Hauge C, Silber J, et al. Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. J Biol Chem. 2005;280(14):13304–13314.
   PubMed Web of Science ®Google Scholar
• Dalby KN, Morrice N, Caudwell FB, et al. Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90RSK that are inducible by MAPK. J Biol Chem. 1998;273(3):1496–1505.
   PubMed Web of Science ®Google Scholar
• Smith JA, Poteet-Smith CE, Malarkey K, et al. Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo. J Biol Chem. 1999;274(5):2893–2898.
   PubMed Web of Science ®Google Scholar
• Kang S, Dong S, Gu TL, et al. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell. 2007;12(3):201–214.
   PubMed Web of Science ®Google Scholar
• Kang S, Dong S, Guo A, et al. Epidermal growth factor stimulates RSK2 activation through activation of the MEK/ERK pathway and src-dependent tyrosine phosphorylation of RSK2 at Tyr-529. J Biol Chem. 2008;283(8):4652–4657.
   PubMed Web of Science ®Google Scholar
• Vaidyanathan H, Ramos JW. RSK2 activity is regulated by its interaction with PEA-15. J Biol Chem. 2003;278(34):32367–32372.
   PubMed Web of Science ®Google Scholar
• Roux PP, Richards SA, Blenis J. Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Mol Cell Biol. 2003;23(14):4796–4804.
   PubMed Web of Science ®Google Scholar
• Jensen CJ, Buch MB, Krag TO, et al. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999;274(38):27168–27176.
   PubMed Web of Science ®Google Scholar
• Cohen MS, Hadjivassiliou H, Taunton J. A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Nat Chem Biol. 2007;3(3):156–160.
   PubMed Web of Science ®Google Scholar
• Zaru R, Ronkina N, Gaestel M, et al. The MAPK-activated kinase RSK controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nat Immunol. 2007;8(11):1227–1235.
   PubMed Web of Science ®Google Scholar
• Zaru R, Edgar AJ, Hanauer A, et al. Structural and functional basis for p38-MK2-activated RSK signaling in toll-like receptor-stimulated dendritic cells. Mol Cell Biol. 2015;35(1):132–140.
   PubMed Web of Science ®Google Scholar
• Eisinger-Mathason TS, Andrade J, Groehler AL, et al. Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. Mol Cell. 2008;31(5):722–736.
   PubMed Web of Science ®Google Scholar
• Gao X, Chaturvedi D, Patel TB. Localization and retention of p90 ribosomal S6 kinase 1 in the nucleus: implications for its function. Mol Biol Cell. 2012;23(3):503–515.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Bjorbaek C, Weremowicz S, et al. RSK3 encodes a novel pp90RSK isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol. 1995;15(8):4353–4363.
   PubMed Web of Science ®Google Scholar
• Chaturvedi D, Poppleton HM, Stringfield T, et al. Subcellular localization and biological actions of activated RSK1 are determined by its interactions with subunits of cyclic AMP-dependent protein kinase. Mol Cell Biol. 2006;26(12):4586–4600.
   PubMed Web of Science ®Google Scholar
• Gao X, Chaturvedi D, Patel TB. p90 ribosomal S6 kinase 1 (RSK1) and the catalytic subunit of protein kinase A (PKA) compete for binding the pseudosubstrate region of PKAR1alpha: role in the regulation of PKA and RSK1 activities. J Biol Chem. 2010;285(10):6970–6979.
   PubMed Web of Science ®Google Scholar
• Leighton IA, Dalby KN, Caudwell FB, et al. Comparison of the specificities of p70 S6 kinase and MAPKAP kinase-1 identifies a relatively specific substrate for p70 S6 kinase: the N-terminal kinase domain of MAPKAP kinase-1 is essential for peptide phosphorylation. FEBS Lett. 1995;375(3):289–293.
   PubMed Web of Science ®Google Scholar
• David JP, Mehic D, Bakiri L, et al. Essential role of RSK2 in c-Fos-dependent osteosarcoma development. J Clin Invest. 2005;115(3):664–672.
   PubMed Web of Science ®Google Scholar
• Elf S, Blevins D, Jin L, et al. p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia. Blood. 2011;117(25):6885–6894.
   PubMed Web of Science ®Google Scholar
• Lin JX, Spolski R, Leonard WJ. Critical role for RSK2 in T-lymphocyte activation. Blood. 2008;111(2):525–533.
   PubMed Web of Science ®Google Scholar
• Moon HG, Yi JK, Kim HS, et al. Phosphorylation of p90RSK is associated with increased response to neoadjuvant chemotherapy in ER-positive breast cancer. BMC Cancer. 2012;12:585.
   PubMed Web of Science ®Google Scholar
• Stratford AL, Reipas K, Hu K, et al. Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers. Stem Cells. 2012;30(7):1338–1348.
   PubMed Web of Science ®Google Scholar
• Clark DE, Poteet-Smith CE, Smith JA, et al. RSK2 allosterically activates estrogen receptor alpha by docking to the hormone-binding domain. EMBO J. 2001;20(13):3484–3494.
   PubMed Web of Science ®Google Scholar
• Joel PB, Smith J, Sturgill TW, et al. pp90RSK1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol. 1998;18(4):1978–1984.
   PubMed Web of Science ®Google Scholar
• Yamashita H, Nishio M, Kobayashi S, et al. Phosphorylation of estrogen receptor alpha serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer. Breast Cancer Res. 2005;7(5):R753–R764.
   PubMed Web of Science ®Google Scholar
• Yamashita H, Nishio M, Toyama T, et al. Low phosphorylation of estrogen receptor alpha (ERalpha) serine 118 and high phosphorylation of ERalpha serine 167 improve survival in ER-positive breast cancer. Endocr Relat Cancer. 2008;15(3):755–763.
   PubMed Web of Science ®Google Scholar
• Jiang J, Sarwar N, Peston D, et al. Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res. 2007;13(19):5769–5776.
   PubMed Web of Science ®Google Scholar
• Smith JA, Poteet-Smith CE, Xu Y, et al. Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res. 2005;65(3):1027–1034.
   PubMed Web of Science ®Google Scholar
• Berman-Booty LD, Knudsen KE. Models of neuroendocrine prostate cancer. Endocr Relat Cancer. 2015;22(1):R33–49.
   PubMed Web of Science ®Google Scholar
• Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298–305.
   PubMed Web of Science ®Google Scholar
• Clark DE, Errington TM, Smith JA, et al. The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Cancer Res. 2005;65(8):3108–3116.
   PubMed Web of Science ®Google Scholar
• Marzuka A, Huang L, Theodosakis N, et al. Melanoma treatments: advances and mechanisms. J Cell Physiol. 2015;230(11):2626–2633.
   PubMed Web of Science ®Google Scholar
• Cho YY, Lee MH, Lee CJ, et al. RSK2 as a key regulator in human skin cancer. Carcinogenesis. 2012;33(12):2529–2537.
   PubMed Web of Science ®Google Scholar
• Cho YY, Yao K, Pugliese A, et al. A regulatory mechanism for RSK2 NH(2)-terminal kinase activity. Cancer Res. 2009;69(10):4398–4406.
   PubMed Web of Science ®Google Scholar
• Zhu Z, Liu W, Gotlieb V. The rapidly evolving therapies for advanced melanoma-Towards immunotherapy, molecular targeted therapy, and beyond. Crit Rev Oncol Hematol. 2016;99:91–99.
   PubMed Web of Science ®Google Scholar
• Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3305–3313.
   PubMed Web of Science ®Google Scholar
• Kang S, Elf S, Lythgoe K, et al. p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells. J Clin Invest. 2010;120(4):1165–1177.
   PubMed Web of Science ®Google Scholar
• Li D, Jin L, Alesi GN, et al. The prometastatic ribosomal S6 kinase 2-cAMP response element-binding protein (RSK2-CREB) signaling pathway up-regulates the actin-binding protein fascin-1 to promote tumor metastasis. J Biol Chem. 2013;288(45):32528–32538.
   PubMed Web of Science ®Google Scholar
• Lara R, Mauri FA, Taylor H, et al. An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis. Oncogene. 2011;30(32):3513–3521.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Yamada N, Tanaka T, et al. Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2. Nat Commun. 2015;6:7679.
   PubMed Web of Science ®Google Scholar
• Bignone PA, Lee KY, Liu Y, et al. RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer. Oncogene. 2007;26(5):683–700.
   PubMed Web of Science ®Google Scholar
• Milosevic N, Kuhnemuth B, Muhlberg L, et al. Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. Neoplasia. 2013;15(12):1354–1362.
   PubMed Web of Science ®Google Scholar
• Arechavaleta-Velasco F, Zeferino-Toquero M, Estrada-Moscoso I, et al. Ribosomal S6 kinase 4 (RSK4) expression in ovarian tumors and its regulation by antineoplastic drugs in ovarian cancer cell lines. Med Oncol. 2016;33(2):11.
   PubMed Web of Science ®Google Scholar
• Lopez-Vicente L, Armengol G, Pons B, et al. Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors. Clin Cancer Res. 2009;15(14):4546–4553.
   PubMed Web of Science ®Google Scholar
• Cai J, Ma H, Huang F, et al. Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 2014;7(8):4959–4970.
   PubMed Web of Science ®Google Scholar
• Dewdney SB, Rimel BJ, Thaker PH, et al. Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers. Clin Cancer Res. 2011;17(8):2120–2129.
   PubMed Web of Science ®Google Scholar
• Li Q, Jiang Y, Wei W, et al. Frequent epigenetic inactivation of RSK4 by promoter methylation in cancerous and non-cancerous tissues of breast cancer. Med Oncol. 2014;31(1):793.
   PubMed Web of Science ®Google Scholar
• Thakur A, Rahman KW, Wu J, et al. Aberrant expression of X-linked genes RbAp46, RSK4, and Cldn2 in breast cancer. Mol Cancer Res. 2007;5(2):171–181.
   PubMed Web of Science ®Google Scholar
• Serra V, Eichhorn PJ, Garcia-Garcia C, et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest. 2013;123(6):2551–2563.
   PubMed Web of Science ®Google Scholar
• Fan L, Li P, Yin Z, et al. Ribosomal s6 protein kinase 4: a prognostic factor for renal cell carcinoma. Br J Cancer. 2013;109(5):1137–1146.
   PubMed Web of Science ®Google Scholar
• Takeishi Y, Huang Q, Abe J, et al. Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc Res. 2002;53(1):131–137.
   PubMed Web of Science ®Google Scholar
• Takahashi E, Abe J, Berk BC. Angiotensin II stimulates p90RSK in vascular smooth muscle cells. A potential Na(+)-H+ exchanger kinase. Circ Res. 1997;81(2):268–273.
   PubMed Web of Science ®Google Scholar
• Takeishi Y, Abe J, Lee JD, et al. Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused guinea pig hearts. Circ Res. 1999;85(12):1164–1172.
   PubMed Web of Science ®Google Scholar
• Garciarena CD, Fantinelli JC, Caldiz CI, et al. Myocardial reperfusion injury: reactive oxygen species vs. NHE-1 reactivation. Cell Physiol Biochem. 2011;27(1):13–22.
   PubMed Web of Science ®Google Scholar
• Itoh S, Ding B, Shishido T, et al. Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium. Circulation. 2006;113(14):1787–1798.
   PubMed Web of Science ®Google Scholar
• Cheng WH, Lu PJ, Ho WY, et al. Angiotensin II inhibits neuronal nitric oxide synthase activation through the ERK1/2-RSK signaling pathway to modulate central control of blood pressure. Circ Res. 2010;106(4):788–795.
   PubMed Web of Science ®Google Scholar
• Doyon P, Servant MJ. Tumor necrosis factor receptor-associated factor-6 and ribosomal S6 kinase intracellular pathways link the angiotensin II AT1 receptor to the phosphorylation and activation of the IkappaB kinase complex in vascular smooth muscle cells. J Biol Chem. 2010;285(40):30708–30718.
   PubMed Web of Science ®Google Scholar
• Le NT, Heo KS, Takei Y, et al. A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation. 2013;127(4):486–499.
   PubMed Web of Science ®Google Scholar
• Heo KS, Le NT, Cushman HJ, et al. Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. J Clin Invest. 2015;125(3):1299–1310.
   PubMed Web of Science ®Google Scholar
• Maekawa N, Abe J, Shishido T, et al. Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury. Circulation. 2006;113(21):2516–2523.
   PubMed Web of Science ®Google Scholar
• Le NT, Takei Y, Shishido T, et al. p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res. 2012;110(4):536–550.
   PubMed Web of Science ®Google Scholar
• Shi X, O’Neill MM, MacDonnell S, et al. The RSK inhibitor BIX02565 limits cardiac ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther. 2016;21(2):177–186.
   PubMed Web of Science ®Google Scholar
• Fryer RM, Muthukumarana A, Chen RR, et al. Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors. J Pharmacol Exp Ther. 2012;340(3):492–500.
   PubMed Web of Science ®Google Scholar
• Moor AN, Gan XT, Karmazyn M, et al. Activation of Na+/H+ exchanger-directed protein kinases in the ischemic and ischemic-reperfused rat myocardium. J Biol Chem. 2001;276(19):16113–16122.
   PubMed Web of Science ®Google Scholar
• Cuello F, Snabaitis AK, Cohen MS, et al. Evidence for direct regulation of myocardial Na+/H+ exchanger isoform 1 phosphorylation and activity by 90-kDa ribosomal S6 kinase (RSK): effects of the novel and specific RSK inhibitor FMK on responses to alpha1-adrenergic stimulation. Mol Pharmacol. 2007;71(3):799–806.
   PubMed Web of Science ®Google Scholar
• Karmazyn M. NHE-1: still a viable therapeutic target. J Mol Cell Cardiol. 2013;61:77–82.
   PubMed Web of Science ®Google Scholar
• Murphy E, Allen DG. Why did the NHE inhibitor clinical trials fail? J Mol Cell Cardiol. 2009;46(2):137–141.
   PubMed Web of Science ®Google Scholar
• Artamonov M, Momotani K, Utepbergenov D, et al. The p90 ribosomal S6 kinase (RSK) is a mediator of smooth muscle contractility. PLoS One. 2013;8(3):e58703.
   PubMed Web of Science ®Google Scholar
• Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389(6654):990–994.
   PubMed Web of Science ®Google Scholar
• Murthy SN, Nossaman BD, Kadowitz PJ. New approaches to the treatment of pulmonary hypertension: from bench to bedside. Cardiol Rev. 2010;18(2):76–84.
   PubMed Web of Science ®Google Scholar
• Li J, Kritzer MD, Michel JJ, et al. Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy. Circ Res. 2013;112(1):128–139.
   PubMed Web of Science ®Google Scholar
• Passariello CL, Gayanilo M, Kritzer MD, et al. p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in alpha-tropomyosin Glu180Gly transgenic mice. Am J Physiol Heart Circulatory Physiol. 2013;305(7):H1010–H1019.
   PubMed Web of Science ®Google Scholar
• Fu B, Kuang E, Li W, et al. Activation of p90 ribosomal S6 kinases by ORF45 of Kaposi’s sarcoma-associated herpesvirus is critical for optimal production of infectious viruses. J Virol. 2015;89(1):195–207.
   PubMed Web of Science ®Google Scholar
• Kuang E, Tang Q, Maul GG, et al. Activation of p90 ribosomal S6 kinase by ORF45 of Kaposi’s sarcoma-associated herpesvirus and its role in viral lytic replication. J Virol. 2008;82(4):1838–1850.
   PubMed Web of Science ®Google Scholar
• Karijolich J, Zhao Y, Peterson B, et al. Kaposi’s sarcoma-associated herpesvirus ORF45 mediates transcriptional activation of the HIV-1 long terminal repeat via RSK2. J Virol. 2014;88(12):7024–7035.
   PubMed Web of Science ®Google Scholar
• Avey D, Tepper S, Li W, et al. Phosphoproteomic analysis of KSHV-infected cells reveals roles of ORF45-activated RSK during lytic replication. PLoS Pathog. 2015;11(7):e1004993.
   PubMed Web of Science ®Google Scholar
• McCoy MW, Marre ML, Lesser CF, et al. The C-terminal tail of Yersinia pseudotuberculosis YopM is critical for interacting with RSK1 and for virulence. Infect Immun. 2010;78(6):2584–2598.
   PubMed Web of Science ®Google Scholar
• Nusrat S, Khan MS, Fazili J, et al. Cirrhosis and its complications: evidence based treatment. World Journal of Gastroenterology. 2014;20(18):5442–5460.
   PubMed Web of Science ®Google Scholar
• Buck M, Chojkier M. A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis. PLoS One. 2007;2(12):e1372.
   PubMed Web of Science ®Google Scholar
• Morales-Ibanez O, Affo S, Rodrigo-Torres D, et al. Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis. Gut. 2015;65(5):840–851.
   PubMed Web of Science ®Google Scholar
• Buck M, Poli V, van der Geer P, et al. Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is required for hepatocyte proliferation induced by TGF alpha. Mol Cell. 1999;4(6):1087–1092.
   PubMed Web of Science ®Google Scholar
• Yang MF, Xie J, Gu XY, et al. Involvement of 90-kuD ribosomal S6 kinase in collagen type I expression in rat hepatic fibrosis. World J Gastroenterol. 2009;15(17):2109–2115.
   PubMed Web of Science ®Google Scholar
• Buck M, Poli V, Hunter T, et al. C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell. 2001;8(4):807–816.
   PubMed Web of Science ®Google Scholar
• Buck M, Chojkier M. C/EBPbeta-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice. PLoS One. 2011;6(10):e25497.
   PubMed Web of Science ®Google Scholar
• Hutchinson J, Fogarty A, Hubbard R, et al. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J: Off J Eur Soc Clin Respir Physiol. 2015;46(3):795–806.
   PubMed Web of Science ®Google Scholar
• Falconer J, Buckley CD. Rheumatoid arthritis. The two faces of RSK2 in hyperplastic disease. Nat Rev Rheumatol. 2015;11(4):203–205.
   PubMed Web of Science ®Google Scholar
• Derer A, Bohm C, Grotsch B, et al. RSK2 controls synovial fibroblast hyperplasia and the course of arthritis. Ann Rheum Dis. 2016;75(2):413–421.
   PubMed Web of Science ®Google Scholar
• Boyer SJ, Gao DA, Guo X, et al. Heterocyclic compounds containing an indole core. Patent No. US 9,150,577 B2. 2015.
   Google Scholar
• De Cesare D, Jacquot S, Hanauer A, et al. RSK-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci USA. 1998;95(21):12202–12207.
   PubMed Web of Science ®Google Scholar
• Taunton J, Cohen M, Shokat K, et al. Selective serine/threonine kinase inhibitors. Patent No. US 7,687,506 B2. 2010.
   Google Scholar
• Hecht SM, Maloney DJ. Synthesis of inhibitors of p90RSK. Patent No. US 7,605,241 B2. 2009.
   Google Scholar
• Smith JA, Hecht SM, Lannigan-Macara DA, et al. Rhamnose substituents of SL0101 and therapeutic use of thereof. Patent No. US 8,426,568 B2. 2013.
   Google Scholar
• Hecht SM, Lannigan-Macara DA, Smith JA, et al. Synthesis and identification of novel RSK-specific inhibitors. Patent No. US 9,040,673 B2. 2015.
   Google Scholar
• Sim T, Lee HS, Ren P, et al. Compounds and compositions as protein kinase inhibitors. Patent No. US 7,371,750 B2. 2008.
   Google Scholar
• Ren P, Xia W, Gray NS, et al. Compounds and compositions as protein kinase inhibitors. Patent No. US 7,623,038 B2. 2008.
   Google Scholar
• Xie Y, Zhang G, Wang X, et al. Compounds and compositions as protein kinase inhibitors. Patent No. US 7,868,018 B2. 2011.
   Google Scholar
• Nagle A, Gray SN, Liu Y, et al. Substituted purrolo[2,3-D]pyrimidines and compositions as protein kinase inhibitors. Patent No. US 8,183,248 B2. 2012.
   Google Scholar
• Wan Y, Mi Y, Fan Y, et al. Compounds and compositions as protein kinase inhibitors. Patent No. US 8,101,608 B2. 2012.
   Google Scholar
• Nagle A, Gray NS. Compounds and compositions as protein kinase inhibitors. Patent No. US 8,592,433 B2. 2013.
   Google Scholar
• Shoemaker R, Cardelina J, Currens M, et al. Kinase inhibitors, compositions thereof, and methods of use therewith. Patent no. US 8,765,802 B2. 2014.
   Google Scholar
• Kim SG, Lee SJ, Park EY, et al. 4,5,6,7-tetrahydro-[1,2]dithiolo[4,3-C]pyridine-3-thione compounds. Patent No. US 7,435,819 B2. 2008.
   Google Scholar
• Kirrane TM, Boyer SJ, Burke J, et al. Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity. Bioorg Med Chem Lett. 2012;22(1):738–742.
   PubMed Web of Science ®Google Scholar
• Najafi A, Sequeira V, Kuster DW, et al. Beta-adrenergic receptor signalling and its functional consequences in the diseased heart. Eur J Clin Invest. 2016;46(4):362–374.
   PubMed Web of Science ®Google Scholar
• Endicott JA, Noble ME, Johnson LN. The structural basis for control of eukaryotic protein kinases. Annu Rev Biochem. 2012;81:587–613.
   PubMed Web of Science ®Google Scholar
• Zuccotto F, Ardini E, Casale E, et al. Through the “gatekeeper door”: exploiting the active kinase conformation. J Med Chem. 2010;53(7):2681–2694.
   PubMed Web of Science ®Google Scholar
• Cohen MS, Zhang C, Shokat KM, et al. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005;308(5726):1318–1321.
   PubMed Web of Science ®Google Scholar
• Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. Science. 2004;303(5665):1800–1805.
   PubMed Web of Science ®Google Scholar
• Bain J, Plater L, Elliott M, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408(3):297–315.
   PubMed Web of Science ®Google Scholar
• Smith JA, Maloney DJ, Hecht SM, et al. Structural basis for the activity of the RSK-specific inhibitor, SL0101. Bioorg Med Chem. 2007;15(14):5018–5034.
   PubMed Web of Science ®Google Scholar
• Utepbergenov D, Derewenda U, Olekhnovich N, et al. Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 A crystal structure of the N-terminal domain of RSK2 with bound inhibitor. Biochemistry. 2012;51(33):6499–6510.
   PubMed Web of Science ®Google Scholar
• Derewenda U, Artamonov M, Szukalska G, et al. Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK): structure of its complex with the N-terminal domain of RSK2 at 1.8 A resolution. Acta Crystallogr D Biol Crystallogr. 2013;69(Pt2):266–275.
   PubMedGoogle Scholar
• Smith JA, Maloney DJ, Clark DE, et al. Influence of rhamnose substituents on the potency of SL0101, an inhibitor of the Ser/Thr kinase, RSK. Bioorg Med Chem. 2006;14(17):6034–6042.
   PubMed Web of Science ®Google Scholar
• Mrozowski RM, Vemula R, Wu B, et al. Improving the affinity of SL0101 for RSK using structure-based design. ACS Med Chem Lett. 2012;4(2):175–179.
   PubMed Web of Science ®Google Scholar
• Li M, Li Y, Mrozowski RM, et al. Synthesis and structure-activity relationship study of 5a-carbasugar analogues of SL0101. ACS Med Chem Lett. 2015;6(1):95–99.
   PubMed Web of Science ®Google Scholar
• Hentschke M, Berneking L, Belmar Campos C, et al. Yersinia virulence factor YopM induces sustained RSK activation by interfering with dephosphorylation. PLoS One. 2010;5:10.
   Web of Science ®Google Scholar
• Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol. 2006;2(7):358–364.
   PubMed Web of Science ®Google Scholar
• Backes A, Zech B, Felber B, et al. Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition. Expert Opin Drug Discov. 2008;3(12):1427–1449.
   PubMed Web of Science ®Google Scholar
• Alton GR, Lunney EA. Targeting the unactivated conformations of protein kinases for small molecule drug discovery. Expert Opin Drug Discov. 2008;3(6):595–605.
   PubMed Web of Science ®Google Scholar
• Okram B, Nagle A, Adrian FJ, et al. A general strategy for creating “inactive-conformation” abl inhibitors. Chem Biol. 2006;13(7):779–786.
   PubMed Web of Science ®Google Scholar
• Sapkota GP, Cummings L, Newell FS, et al. BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J. 2007;401(1):29–38.
   PubMed Web of Science ®Google Scholar
• Duran A, Linz G. Process for the manufacture of fused piperazin-2-one derivatives. Patent application No. US 2006/0122393 A1. 2006.
   Google Scholar
• Aronchik I, Appleton BA, Basham SE, et al. Novel potent and selective inhibitors of p90 ribosomal S6 kinase reveal the heterogeneity of RSK function in MAPK-driven cancers. Mol Cancer Res. 2014;12(5):803–812.
   PubMed Web of Science ®Google Scholar
• Jain R, Mathur M, Lan J, et al. Discovery of potent and selective RSK inhibitors as biological probes. J Med Chem. 2015;58(17):6766–6783.
   PubMed Web of Science ®Google Scholar
• Kang KW, Kim YG, Cho MK, et al. Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation. FASEB J: Off Publ Fed Am Soc Exp Biol. 2002;16(14):1988–1990.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Munday R. Dithiolethiones for cancer chemoprevention: where do we stand? Mol Cancer Ther. 2008;7(11):3470–3479.
   PubMed Web of Science ®Google Scholar
• Kim SG, Kim YM, Choi JY, et al. Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial. J Pharm Pharmacol. 2011;63(5):627–635.
   PubMed Web of Science ®Google Scholar
• Kodama H, Fukuda K, Pan J, et al. Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. Am J Physiol Heart Circul Physiol. 2000;279(4):H1635–H1644.
   PubMed Web of Science ®Google Scholar
• Sadoshima J, Qiu Z, Morgan JP, et al. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. Circ Res. 1995;76(1):1–15.
   PubMed Web of Science ®Google Scholar
• Seko Y, Tobe K, Ueki K, et al. Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes. Circ Res. 1996;78(1):82–90.
   PubMed Web of Science ®Google Scholar
• Martinez EC, Passariello CL, Li J, et al. RSK3: a regulator of pathological cardiac remodeling. IUBMB Life. 2015;67(5):331–337.
   PubMed Web of Science ®Google Scholar
• Passariello CL, Li J, Dodge-Kafka K, et al. mAKAP-a master scaffold for cardiac remodeling. J Cardiovasc Pharmacol. 2015;65(3):218–225.
   PubMed Web of Science ®Google Scholar
• Kapiloff MS, Li J, Kritzer M, et al. Treatment of heart disease by inhibition of the action of ribosomal S6 kinase 3 (RSK3). Patent No. US 9,132,174 B2. 2015.
   Google Scholar
• Chaturvedi D, Cohen MS, Taunton J, et al. The PKARIalpha subunit of protein kinase A modulates the activation of p90RSK1 and its function. J Biol Chem. 2009;284(35):23670–23681.
   PubMed Web of Science ®Google Scholar
• Edgar AJ, Trost M, Watts C, et al. A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the RSK inhibitor BI-D1870. Biosci Rep. 2014;34:e00091.
   PubMed Web of Science ®Google Scholar
• Doehn U, Hauge C, Frank SR, et al. RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. Mol Cell. 2009;35(4):511–522.
   PubMed Web of Science ®Google Scholar
• Mrozowski RM, Sandusky ZM, Vemula R, et al. De novo synthesis and biological evaluation of C6ʹ’-substituted C4ʹ’-amide analogues of SL0101. Org Lett. 2014;16(22):5996–5999.
   PubMed Web of Science ®Google Scholar
• Takada I, Yogiashi Y, Makishima M. The ribosomal S6 kinase inhibitor BI-D1870 ameliorated experimental autoimmune encephalomyelitis in mice. Immunobiology. 2016;221(2):188–192.
   PubMed Web of Science ®Google Scholar
• Uehling DE, Harris PA. Recent progress on MAP kinase pathway inhibitors. Bioorg Med Chem Lett. 2015;25(19):4047–4056.
   PubMed Web of Science ®Google Scholar
• Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discovery. 2014;13(12):928–942.
   PubMed Web of Science ®Google Scholar
• Hoeflich KP, O’Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–4664.
   PubMed Web of Science ®Google Scholar
• Turke AB, Song Y, Costa C, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 2012;72(13):3228–3237.
   PubMed Web of Science ®Google Scholar
• Peeper DS, Smit A, Vogel CJ. p90RSK in combination with RAF/ERK/MEK. Patent application WO2015041534 A1. 2015.
   Google Scholar