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The specificities of protein kinase inhibitors: an update
Open accessAbstract
We have previously examined the specificities of 28 commercially available compounds, reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases [Davies, Reddy, Caivano and Cohen (2000) Biochem. J. 351, 95—105]. In the present study, we have extended this analysis to a further 14 compounds. Of these, indirubin-3′-monoxime, SP 600125, KT 5823 and ML-9 were found to inhibit a number of protein kinases and conclusions drawn from their use in cell-based assays are likely to be erroneous. Kenpaullone, Alsterpaullone, Purvalanol, Roscovitine, pyrazolopyrimidine 1 (PP1), PP2 and ML-7 were more specific, but still inhibited two or more protein kinases with similar potency. Our results suggest that the combined use of Roscovitine and Kenpaullone may be useful for identifying substrates and physiological roles of cyclin-dependent protein kinases, whereas the combined use of Kenpaullone and LiCl may be useful for identifying substrates and physiological roles of glycogen synthase kinase 3. The combined use of SU 6656 and either PP1 or PP2 may be useful for identifying substrates of Src family members. Epigallocatechin 3-gallate, one of the main polyphenolic constituents of tea, inhibited two of the 28 protein kinases in the panel, dual-specificity, tyrosine-phosphorylated and regulated kinase 1A (DYRK1A; IC50 = 0.33μM) and p38-regulated/activated kinase (PRAK; IC50 = 1.0μM).
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“The latest result demonstrates that the JNK specificity of SP600125 is not so excellent and this compound inhibits some protein kinases with similar or greater potency than JNK (Bain et al , 2003).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Bain et al , 2003
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Specificity and mechanism of action of some commonly used protein kinase inhibitors
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MethodMyosin II Activity Softens Cells in Suspension
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“ML7 directly targets the myosin light chain kinase (MLCK) pathway by inhibiting its activity (23).”
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Phosphorylation of STIM1 at ERK1/2 target sites modulates store-operated calcium entry
Pozo‐Guisado, E., Campbell, D. G., Deák, M., Alvarez, A. M., Morrice, N. A., Álvarez, I. S., Alessi, D. R., & Martı́n-Romero, F. J. (2010) · Journal of Cell Science · doi:10.1242/jcs.067215 · Cited by 115
“Other experimental conditions were as described (Bain et al., 2003; Bain et al., 2007).”
MethodLi, C., Ge, B., Nicotra, M. L., Stern, J. N. H., Kopcow, H. D., Chen, X., & Strominger, J. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712310105 · Cited by 114
“However, the high concentration of the JNK inhibitor SP600125 used (25 M) is far above that which is selective for JNK (40), and the concentration used decreases cell viability and induces apoptosis (41).”
BackgroundMethodDYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis
Fernández, P., Zahonero, C., & Sánchez‐Gómez, P. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723548.2014.970048 · Cited by 110
Polycystin-1 Activates the Calcineurin/NFAT (Nuclear Factor of Activated T-cells) Signaling Pathway
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“78 To a lesser extent ( ~ 50%), EGCG also inhibited ERK2, ROCK2, and PDK1.”
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“A number of embryos (20-40) from a transgenic mating pair were collected and incubated at 28.”
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“Although we interpret this result to signify that JNK pathway deregulation due to Nf1 heterozygosity is sufficient to lead to microglia activation, SP600125 has been reported to inhibit other signaling kinases, including serum-regulated and glucocorticoid-regulated kinase, p70-ribosomal S6 kinase, AMP-dependent protei…”
BackgroundShepherd, E. G., Zhao, Q., Welty, S. E., Hansen, T. N., Smith, C. V., & Liu, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408444200 · Cited by 111
Targeting cell cycle and apoptosis for the treatment of human malignancies
Senderowicz, A. M. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2004.09.014 · Cited by 110
Endogenous and synthetic inhibitors of the Src-family protein tyrosine kinases
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10-Iodo-11 H -indolo[3,2- c ]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A
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Roscovitine Reduces Neuronal Loss, Glial Activation, and Neurologic Deficits after Brain Trauma
Hilton, G. D., Stoica, B. A., Byrnes, K. R., & Faden, A. I. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.75 · Cited by 108
“It poorly inhibits CDKs 4 and 6 (Meijer et al, 1997) and does not significantly inhibit members of most other kinase families (Bain et al, 2003).”
Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase
Gambaryan, S., Geiger, J., Schwarz, U. R., Butt, E., Begonja, A., Obergfell, A., & Walter, U. (2004) · Blood · doi:10.1182/blood-2003-09-3349 · Cited by 107
Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases
Backlund, M., & Ingelman‐Sundberg, M. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.05.010 · Cited by 107
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“Firstly, CK1y/ CK1q, a key determinant of circadian period (21, 43–45), could be inhibited by Seliciclib (19, 20, 46).”
BackgroundCell cycle molecules and vertebrate neuron death: E2F at the hub
Greene, L. A., Biswas, S. C., & Liu, D. X. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401341 · Cited by 108
Src Family Kinases: Potential Targets for the Treatment of Human Cancer and Leukemia
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“Two recent publications suggest that this is a rather common occurrence when working with small molecule kinase inhibitors [157, 158], questioning not only results on Src signalling but also on the function of many other kinases obtained by using small molecule kinase inhibitors.”
BackgroundAn Update on the Health Benefits of Green Tea
Reygaert, W. C. (2017) · Beverages · doi:10.3390/beverages3010006 · Cited by 106
“EGCG Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) Inhibits DYRK1A Decreased cell proliferation [40]”
BackgroundGSK3β Regulates Myelin-Dependent Axon Outgrowth Inhibition through CRMP4
Alabed, Y. Z., Pool, M., Tone, S. O., Sutherland, C. D., & Fournier, A. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.6154-09.2010 · Cited by 105
“For outgrowth assays using pharmacologic inhibitors, SB216763, SB415286 (Sigma), 6-bromoindirubin-3 -acetoxime (EMD Biosciences), and CT99021 (generously provided by Dr. Rodolfo Marquez, School of Life Sciences, University of Dundee, Dundee, Scotland), were added to cultures after seeding.”
BackgroundInfluentialMadgwick, S., Levasseur, M., & Jones, K. T. (2005) · Journal of Cell Science · doi:10.1242/jcs.02506 · Cited by 105
Chen, B., Pan, H., Zhu, L., Deng, Y., & Pollard, J. W. (2005) · Molecular Endocrinology · doi:10.1210/me.2004-0274 · Cited by 105
“To determine whether GSK-3 is the central kinase regulating the localization of cyclin D1, we treated mice with an intraluminal injection of LiCl, a specific inhibitor of GSK-3 (58).”
Aggregated IgG inhibits the differentiation of human fibrocytes
Pilling, D., Tucker, N. M., & Gomer, R. H. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0805456 · Cited by 104
“cific SRTK inhibitor PP2 or the specific Syk inhibitor 3-(1methyl-1H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1Hindole-5-sulfonamide before the addition of SAP or aggregated IgG [58, 59].”
BackgroundHNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells
Iles, K. E., Dickinson, D. A., Wigley, A. F., Welty, N. E., Blank, V., & Forman, H. J. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.03.026 · Cited by 105
“First, a rigorous study of the specificity of 28 commercially available inhibitors has identified multiple cellular effects of SP600125 and has brought its specificity into question [49].”
BackgroundBulayeva, N. N., Gametchu, B., & Watson, C. S. (2004) · Steroids · doi:10.1016/j.steroids.2003.12.003 · Cited by 103
“PP2’s action as an ERK stimulator can possibly be explained by the ability of this compound to affect enzymes other than Src kinases at a concentration of 10 μM [6,51].”
BackgroundDorin, D., Semblat, J., Poullet, P., Alano, P., Goldring, J. P. D., Whittle, C. M., Patterson, S., Chakrabarti, D., & Doerig, C. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04393.x · Cited by 103
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“For example, in addition to inhibiting SFKs, the commonly used SFK inhibitor PP1 can also inhibit CSK, casein kinase I, and the stress-activated protein kinases (Bain et al. 2003).”
BackgroundDependence of Cisplatin-Induced Cell Death In Vitro and In Vivo on Cyclin-Dependent Kinase 2
Price, P. M., Yu, F. Z., Kaldis, P., Aleem, E. A., Nowak, G. D. A., Safirstein, R. L., & Megyesi, J. K. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006020162 · Cited by 101
Peineau, S., Nicolas, C. S., Bortolotto, Z. A., Bhat, R. V., Ryves, W. J., Harwood, A. J., Dournaud, P., Fitzjohn, S. M., & Collingridge, G. L. (2009) · Molecular Brain · doi:10.1186/1756-6606-2-22 · Cited by 101
“These data come from kinase assays performed at the same or a similar concentration as used in our experiments, except for AR-164 and KT5720 for which the kinase selectivity has been evaluated for a concentration 10-fold higher [24,54-58].”
Mitchell, D. J., Blasier, K. R., Jeffery, E. D., Ross, M. W., Pullikuth, A., Suo, D., Park, J., Smiley, W. R., Lo, K. W. ‐., Shabanowitz, J., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5599-11.2012 · Cited by 100
“…of ERK1/2 was obtained by the finding that PD 184352, which is structurally unrelated to UO126 and inhibits MEK1/2 activation in a different way (Davies et al., 2000; Bain et al., 2003), also blocked the neurotrophin-stimulated phosphorylation in PC12 cells and activation of ERK1/2 (Fig.”
BackgroundSmall molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells
Lange, C. M., Mix, E., Frahm, J., Glass, A. S., Müller, J. A., Schmitt, O., Schmöle, A., Klemm, K., Ortinau, S., Hübner, R., et al. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.10.076 · Cited by 100
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Diverse Roles for MAPK Signaling in Circadian Clocks
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Bianchi, M., Lucchini, S. D., Marin, O., Turner, D. L., Hanks, S. K., & Villa-Moruzzi, E. (2005) · Biochemical Journal · doi:10.1042/bj20050282 · Cited by 100
Characterization of a Protein Kinase B Inhibitor In Vitro and in Insulin-Treated Liver Cells
Logie, L., Ruiz‐Alcaraz, A. J., Keane, M. P., Woods, Y. L., Bain, J., Márquez, R., Alessi, D. R., & Sutherland, C. D. (2007) · Diabetes · doi:10.2337/db07-0343 · Cited by 100
“provided (40), and complete assay conditions are provided in supplementary”
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Marston, D. J., Higgins, C. D., Peters, K. A., Cupp, T. D., Dickinson, D. J., Pani, A. M., Moore, R. P., Cox, A. H., Kiehart, D. P., & Goldstein, B. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.010 · Cited by 99
“Although we see a weak effect on gastrulation in LET-502- (ROCK-)depleted embryos, suggesting a possible role, and we previously have seen inhibition of gastrulation using MLCK inhibitors (albeit at high enough concentrations to cause non-specific effects [10, 42]), our evidence would suggest that MRCK-1 is the primar…”
BackgroundDai, N., Christiansen, J., Nielsen, F. C., & Avruch, J. (2013) · Genes & Development · doi:10.1101/gad.209130.112 · Cited by 99
“To screen for protein kinases capable of phosphorylating the IMP1 Ser–Pro sites, we treated RD cells with relatively high concentrations of several agents capable of inhibiting a variety of proline-directed kinases, including MAPKs, cdks, GSK3, andmTOR (Davies et al. 2000; Bain et al. 2003; Thoreen et al. 2009).”
BackgroundPreclinical efficacy on GSK‐3 inhibitors: Towards a future generation of powerful drugs
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“Although, roscovitine (seliciclib), claimed as a dual CDK/GSK-3 inhibitor,(43) has recently entered in human clinical trials for IgA nephropathy treatment, its inhibition of GSK-3 is up to date not clear.(44) Myeloma cell growth is regulated through Akt/GSK-3/forkhead signaling pathway.”
Green tea compounds in breast cancer prevention and treatment
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The role of JNK in prostate cancer progression and therapeutic strategies
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Bim Is a Direct Target of a Neuronal E2F-Dependent Apoptotic Pathway
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“Although cdk inhibitors block induction of Bim protein and Bim reporter activity, it is possible that such actions are attributable to nonspecific actions of these molecules (Bain et al., 2003).”
Knockaert, M., Blondel, M., Bach, S., Leost, M., Elbi, C., Hager, G. L., Nagy, S. R., Han, D., Denison, M. S., Ffrench, M., et al. (2004) · Oncogene · doi:10.1038/sj.onc.1207535 · Cited by 98
“E, GSK-3, and other kinase targets (Leclerc et al., 2001; Bain et al., 2003).”
Conditional Control of Protein Function
Banaszynski, L. A., & Wandless, T. J. (2006) · Chemistry & Biology · doi:10.1016/j.chembiol.2005.10.010 · Cited by 97
Affinity Profiling of the Cellular Kinome for the Nucleotide Cofactors ATP, ADP, and GTP
Becher, I., Savitski, M. M., Savitski, M. F., Hopf, C., Bantscheff, M., & Drewes, G. (2012) · ACS Chemical Biology · doi:10.1021/cb3005879 · Cited by 100
The Coming of Age of Phosphoproteomics—from Large Data Sets to Inference of Protein Functions
Roux, P. P., & Thibault, P. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r113.032862 · Cited by 96
“Pharmacological inhibitors are indispensable tools for acutely inhibiting the activity of a particular protein kinase; however, these tools have varying specificities and potencies (66).”
BackgroundCRF signaling: molecular specificity for drug targeting in the CNS
ARZT, E. S., & Holsboer, F. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.08.007 · Cited by 96
Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors
Valés‐Gómez, M., Chisholm, S. E., Cassady-Cain, R. L., Roda‐Navarro, P., & Reyburn, H. T. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2973 · Cited by 97
“Indeed, treatment with LiCl and kenpaullone, two structurally different inhibitors of GSK-3 kinase activity ( 35 ), reduced MICA/MICB expression induced by butyrate (Fig. 5C) and valproate (not shown).”
BackgroundModulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition
Horton, E. R., Humphries, J. D., Stutchbury, B., Jacquemet, G., Ballestrem, C., Barry, S. T., & Humphries, M. J. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201508080 · Cited by 94
Posttranslational modifications of cardiac ryanodine receptors: Ca2+ signaling and EC-coupling
Niggli, E., Ullrich, N. D., Gutierrez, D. A., Kyrychenko, S., Polaková, E., & Shirokova, N. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.08.016 · Cited by 99
“This includes activators and inhibitors for protein kinases [53], phosphatases and NO synthases [54].”
Peifer, C., Selig, R., Kinkel, K., Ott, D., Totzke, F., Schächtele, C., Heidenreich, R., Röcken, M., Schollmeyer, D., & Laufer, S. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8001185 · Cited by 95
Kuo, G., DeAngelis, A., Emanuel, S. L., Wang, A., Zhang, Y., Connolly, P. J., Chen, X., Gruninger, R. H., Rugg, C. A., Fuentes‐Pesquera, A. R., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm040214h · Cited by 96
Role of JNK in Mammary Gland Development and Breast Cancer
Cellurale, C., Girnius, N., Jiang, F., Cavanagh, J., Lu, S., Garlick, D. S., Mercurio, A. M., & Davis, R. J. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1628 · Cited by 95
“However, SP600125 exhibits poor selectivity for JNK (16).”
Murphy, S., Martin, S., & Parton, R. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015030 · Cited by 94
“Each of these reagents have different documented primary targets and a number of listed off-target effects [36,37,38,39].”
Identification and Characterization of a Novel Class of c-Jun N-terminal Kinase Inhibitors
Schepetkin, I. A., Kirpotina, L. N., Khlebnikov, А. I., Hanks, T. S., Kochetkova, I., Pascual, D., Jutila, M. A., & Quinn, M. T. (2012) · Molecular Pharmacology · doi:10.1124/mol.111.077446 · Cited by 99
Copple, I. M., Goldring, C. E., Kitteringham, N. R., & Park, B. K. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-00663-0_9 · Cited by 98
Malaria: Targeting parasite and host cell kinomes
Doerig, C., Abdi, A. I., Bland, N. D., Eschenlauer, S. C. P., Dorin, D., Fennell, C., Halbert, J., Holland, Z., Nivez, M.-P., Semblat, J., et al. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.10.009 · Cited by 93
Yin, X., Jin, N., Shi, J., Zhang, Y., Wu, Y., Gong, C.-X., Iqbal, K., & Liu, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-00682-y · Cited by 93
Scales, T., Lin, S., Kraus, M., Goold, R., & Gordon-Weeks, P. (2009) · Journal of Cell Science · doi:10.1242/jcs.040162 · Cited by 4
“There are five phosphorylation sites in the Ballif et al. (Ballif et al., 2004) embryonic mouse brain data set that we did not find in our neonatal rat MAP1B, despite sequencing peptides containing four of these sites (Table 1).”
InfluentialJNK Pathway in CNS Pathologies
Corrales, T. D. L. R., Losada‐Pérez, M., & Casas‐Tintó, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083883 · Cited by 92
“However, several studies reported that this ATP-competitive inhibitor is not selective for JNK isoforms, and binds to other JNK nonrelated kinases [61].”
BackgroundMeggio, F., Pagano, M. A., Moro, S., Zagotto, G., Ruzzene, M., Sarno, S., Cozza, G., Bain, J., Elliott, M., Deana, A. D., et al. (2004) · Biochemistry · doi:10.1021/bi048999g · Cited by 91
“... protein kinase B (also called Akt), (16) SGK, serum- and glucocorticoid-induced kinase, (17) p70S6K, ribosomal protein S6 kinase, (18) GSK3‚, glycogen synthase kinase 3, (19) ROCKII, Rho-dependent protein kinase, (20) AMPK, AMP-activated protein kinase, (21) CHK1, checkpoint kinase, (22) PHK, phosphorylase kinase,…”
Self-citationCatuara‐Solarz, S., Espinosa‐Carrasco, J., Erb, I., Langohr, K., González, J. R., Notredame, C., & Dierssen, M. (2016) · eNeuro · doi:10.1523/eneuro.0103-16.2016 · Cited by 90
“In the hippocampus, Dyrk1A heterozygous mice show a significant reduction in hippocampal thickness, accompanied by decreases in cell number in CA1, CA2, CA3, and DG (Arqué et al., 2008).”
BackgroundInfluentialLin, Y., Cheng, J., Liang, L., Ko, C., Lo, Y., & Lu, P. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04792.x · Cited by 90
Drosten, M., & Pützer, B. M. (2006) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0610 · Cited by 90
“The pyrazolopyrimidines PP1 and PP2 are potent inhibitors of the Src tyrosine kinase family, but also possess inhibitory effects on other tyrosine kinases, including RET ( Table 1 )”
Investigating Wnt signaling: a chemogenomic safari
McMillan, M., & Kahn, M. (2005) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03613-5 · Cited by 91
Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt
Pratt, M. R., Schwartz, E. C., & Muir, T. W. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700816104 · Cited by 89
Regulation of cell proliferation and survival: Convergence of protein kinases and caspases
Duncan, J. S., Turowec, J. P., Vilk, G., Li, S. S. ‐., Gloor, G. B., & Litchfield, D. W. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.11.001 · Cited by 91
Reciprocal Encoding of Signal Intensity and Duration in a Glucose-Sensing Circuit
Fu, Y., Lim, S., Urano, D., Tunc‐Ozdemir, M., Phan, N. G., Elston, T. C., & Jones, A. M. (2014) · Cell · doi:10.1016/j.cell.2014.01.013 · Cited by 89
“Among 42 kinase inhibitors comprehensively examined, the specificity of PP1 was relatively specific, although PP1 still inhibited 4 of 28 tested mammalian kinases (Bain et al., 2003; Davies et al., 2000).”
BackgroundOximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential
Schepetkin, I. A., Плотников, М. Б., Khlebnikov, А. I., Плотникова, Т. М., & Quinn, M. T. (2021) · Biomolecules · doi:10.3390/biom11060777 · Cited by 88
“Compound 1 can inhibit several different kinases, including CDK1, CDK2, CDK5, CDK9, GSK-3α/β, PhK, FLT3, AMP-activated protein kinase (AMPK), Lck, and serumand glucocorticoid-induced kinase (SGK) [17,37,40,43,44,49,50] (Figure 3).”
InfluentialInhibition of TNFα-induced activation of nuclear factor κB by kava (Piper methysticum) derivatives
Folmer, F., Blasius, R., Morceau, F., Tabudravu, J., Dicato, M., Jaspars, M., & Diederich, M. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.12.032 · Cited by 80
Bartholome, A., Kampkötter, A., Tanner, S., Sies, H., & Klotz, L. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.05.024 · Cited by 89
Barthet, G., Framery, B., Gaven, F., Pellissier, L. P., Reiter, É., Claeysen, S., Bockaert, J., & Dumuis, A. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-12-1080 · Cited by 88
“Moreover, pretreatment of neurons with 10 M PP2 markedly decreased phosphorylation of p-ERK1/2 (Figure 9B).”
InfluentialSuh, H.-S., Kim, M.-O., & Lee, S. C. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2712 · Cited by 90
“The concentrations of the inhibitors were chosen based on their reported IC50 for their specific substrates (45, 46).”
BackgroundMethodKinase-Dependent Differentiation of a Retinal Ganglion Cell Precursor
Frassetto, L. J., Schlieve, C. R., Lieven, C. J., Utter, A. A., Jones, M. V., Agarwal, N. A., & Levin, L. A. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-0340 · Cited by 87
Zhou, X., Liu, Y., You, J., Zhang, H., Zhang, X., & Ye, L. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.05.028 · Cited by 88
“MCF-7 cells and LM-MCF-7 cells were treated with 20 lM ML-7 according to reports [12,21] and plated on a 0.”
MethodMigration of Airway Smooth Muscle Cells
Gerthoffer, W. T. (2007) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200704-051vs · Cited by 89
“The small molecule inhibitors are quite effective in cell cultures and reasonably selective for the target kinases (67).”
BackgroundGhosh, J. C., & Altieri, D. C. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-2624 · Cited by 87
“Although both classes of antagonists reproduced the up-regulation of p53 and the activation of p53-dependent apoptosis, purvalanol A, a 2,6,9-trisubstituted ATP inhibitor of p34cdc2 (18), as well as Cdk2 ( 7 ), provided the most robust”
BackgroundMethodResultInfluentialSkerratt, S. E., Andrews, M. D., Bagal, S. K., Bilsland, J., Brown, D., Bungay, P. J., Cole, S. M., Gibson, K. R., Jones, R. M. H., Morao, I., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00850 · Cited by 87
Schepetkin, I. A., Khlebnikov, А. I., Potapov, А. S., Kovrizhina, A. R., Matveevskaya, V. V., Belyanin, M. L., Atochin, D. N., Zanoza, S. O., Gaidarzhy, N. M., Lyakhov, S. А., et al. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.10.023 · Cited by 88
“Upstream kinases of the MAPK cascade (MKK4 and MKK7) phosphorylate and activate JNK [18], whereas transcription factors such as c-Jun, specificity protein 1 (Sp1), activating transcription factor 2 (ATF2), and nuclear factors of activated T-cells (NFATc2 and NFATc3) are substrates for phosphorylation-activated JNKs [5…”
BackgroundInfluentialGSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways
Demuro, S., Martino, R. M. C. D., Ortega, J. A., & Cavalli, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169098 · Cited by 88
ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest
Todd, D. E., Densham, R. M., Molton, S. A., Balmanno, K., Newson, C., Weston, C. R., Garner, A. P., Scott, L. A., & Cook, S. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207467 · Cited by 86
Park, J., Oh, Y., & Chung, K. C. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.1.006 · Cited by 86
“example, two putative DYRK1A inhibitors were recently developed from in vitro high-throughput screening (97, 98).”
Background
Metadata
- Authors
- BAIN, J., McLAUCHLAN, H., ELLIOTT, M., & COHEN, P.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- BAIN, Jenny
- McLAUCHLAN, Hilary
- ELLIOTT, Matthew
- COHEN, Philip
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-04-01
- Volume
- 371
- Issue
- 1
- Pages
- 199-204
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223271
- OpenAlex
- W2011588737
- Cited by
- 1,369
- References
- 42
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 12 · 2023: 16 · 2022: 26 · 2021: 35 · 2020: 28 · 2019: 38 · 2018: 42 · 2017: 48 · 2016: 42 · 2015: 44 · 2014: 52 · 2013: 66 · 2012: 70
- FWCI
- 43.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- protein kinase inhibitors, kinase selectivity, serine/threonine kinase, indirubin-3'-monoxime, KT5823, ML-9, kenpaullone, roscovitine, pyrazolopyrimidines, cyclin-dependent kinases, glycogen synthase kinase-3, Src family kinases, epigallocatechin gallate, DYRK1A, kinase substrate identification
- MeSH terms
- Alkaloids, Anthracenes, Azepines, Benzazepines, Carbazoles, Catechin, Enzyme Inhibitors, Indoles, Kinetin, Naphthalenes, Oximes, Purines, Pyrazoles, Pyrimidines, Substrate Specificity, Signal Transduction, Cyclin-Dependent Kinases, src-Family Kinases, Mitogen-Activated Protein Kinases, Glycogen Synthase Kinase 3, Protein Kinase Inhibitors, JNK Mitogen-Activated Protein Kinases
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