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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A recent study found that SP600125 is not highly JNK-specific and that it blocks some protein kinases as strongly or more strongly than JNK.
“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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“However, it is to note that SP600125 has shown a limited specificity toward JNK, as also inhibits not only MKK4 and MKK7, but also other protein kinases unrelated to JNK, such as SGK, p70 ribosomal protein S6 kinase (S6K1), AMPK, CDK2, CK1d, and DYRK1A (Bain et al., 2003).”
BackgroundSu, L., Nalle, S. C., Shen, L., Turner, E. S., Singh, G., Breskin, L. A., Khramtsova, E. A., Khramtsova, G. F., Tsai, P., Fu, Y., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.04.011 · Cited by 393 · see citing works
New approaches to molecular cancer therapeutics
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“Nevertheless, in vitro selectivity profiling using panels of isolated kinase”
BackgroundPuttini, M., Coluccia, A. M. L., Boschelli, F., Cleris, L., Marchesi, E., Donella‐Deana, A., Ahmed, S., Redaelli, S., Piazza, R., Magistroni, V., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1199 · Cited by 376 · see citing works
“Procedures for purification and assay of 30 of the 52kinases have been described (31, 32 ). Kinase assays were done using ATP concentrations close to the Km value for each kinase.”
MethodMechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure
Fernández-Sánchez, M. E., Barbier, S., Whitehead, J., Béalle, G., Michel, A., Latorre-Ossa, H., Rey, C., Fouassier, L., Clapéron, A., Brullé, L., et al. (2015) · Nature · doi:10.1038/nature14329 · Cited by 371 · see citing works
Regulation of JNK and p38 MAPK in the immune system: Signal integration, propagation and termination
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“However, for mechanistic studies, pharmacological inhibitors are well known to cause non-specific or non-physiological effects [16,17].”
BackgroundCytoskeletal Regulation of Epithelial Barrier Function During Inflammation
Ivanov, A. I., Parkos, C. A., & Nusrat, A. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100168 · Cited by 366 · see citing works
“While inhibiting MLCK, these ATP-competitive agents also inactivate other kinases.(101) ML-9, for example, has been shown to inhibit ROCK-II activity more potently than MLCK.”
BackgroundInfluentialA systematic interaction map of validated kinase inhibitors with Ser/Thr kinases
Fedorov, O., Marsden, B. D., Pogačić, V., Rellos, P., Müller, S., Bullock, A. N., Schwaller, J., Sundström, M., & Knapp, S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708800104 · Cited by 361 · see citing works
L1000CDS2: LINCS L1000 characteristic direction signatures search engine
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Roscovitine Targets, Protein Kinases and Pyridoxal Kinase
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GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS
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“Systemic analysis that profiled protein kinase inhibitors also confirmed the high selectivity of CHIRs toward GSK-3 (Bain et al., 2003, 2007).”
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“SP600125 also partially inhibited phosphorylation at these sites; this reagent inhibits JNK, but also other kinases, including CDKs (Bain et al, 2003).”
BackgroundCell Apoptosis: Requirement of H2AX in DNA Ladder Formation, but Not for the Activation of Caspase-3
Lu, C., Zhu, F., Cho, Y., Tang, F., Zykova, T. A., Ma, W., Bode, A. M., & Dong, Z. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.05.023 · Cited by 354 · see citing works
“Some reports (Bain et al., 2003; Davies et al., 2000) indicated that SP600125 is a non-specific inhibitor in vitro and affects other kinases such as p70 S6K.”
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JNK signalling in cancer: in need of new, smarter therapeutic targets
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“MAPKs are activated via a BJP British Journal ofPharmacology DOI:10.1111/bph.12432 www.brjpharmacol.org 24 British Journal of Pharmacology (2014) 171 24–37 © 2013 The British Pharmacological Society kinase signalling cascade in which a MAP3K activates a MAP2K, that in turn activates a MAPK.”
BackgroundInfluentialMurray, J. T., CAMPBELL, D. G., Morrice, N. A., Auld, G. C., Shpiro, N., Márquez, R., Peggie, M. W., Bain, J., Bloomberg, G. B., Grahammer, F., et al. (2004) · Biochemical Journal · doi:10.1042/bj20041057 · Cited by 341 · see citing works
Self-citationde Vries, E., Tscherne, D. M., Wienholts, M. J., Jiménez, V. C., Scholte, F. E. M., García‐Sastre, A., Rottier, P. J. M., & de Haan, C. A. M. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1001329 · Cited by 339 · see citing works
“MLCK inhibitors ML-7 and ML-9 have been reported to be highly specific for their target kinase [30].”
Nuclear and cytosolic JNK signalling in neurons
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An efficient proteomics method to identify the cellular targets of protein kinase inhibitors
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Strategies to overcome resistance to targeted protein kinase inhibitors
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“This can be done in high throughput by screening large collections of recombinant kinases against drug candidates in paralle”
BackgroundThe purines: Potent and versatile small molecule inhibitors and modulators of key biological targets
Legraverend, M., & Grierson, D. S. (2006) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2005.12.060 · Cited by 332 · see citing works
The Nrf2–Keap1 defence pathway: Role in protection against drug-induced toxicity
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Self-citationActivation-Loop Autophosphorylation Is Mediated by a Novel Transitional Intermediate Form of DYRKs
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Mitogen-Activated Protein Kinases and Their Role in Radiation Response
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“Preclinical observations made with a JNK inhibitor (SP600125) are likely to be less informative regarding the biological roles of JNK due to the considerable off-target activity of this compound.(42) One JNK inhibitor, CC-401, is however in phase II evaluations in acute myelogenous leukemia and has also been considere…”
BackgroundMyosin light chain kinase: pulling the strings of epithelial tight junction function
Cunningham, K. E., & Turner, J. R. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06526.x · Cited by 345 · see citing works
The Many Faces of H89: A Review
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Multiple Wnts are involved in Hydra organizer formation and regeneration
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“(ii) Treatment with alsterpaullone, a specific inhibitor of GSK-3β (Leost et al., 2000; Bain et al., 2003), results in the body column, acquiring organizer characteristics as measured by transplantation experiments (Broun et al.”
BackgroundHui, L., Zatloukal, K., Scheuch, H., Stępniak-Konieczna, E., & Wagner, E. F. (2008) · Journal of Clinical Investigation · doi:10.1172/jci37156 · Cited by 308 · see citing works
BIRB796 Inhibits All p38 MAPK Isoforms in Vitro and in Vivo
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Self-citationMechanisms of drug inhibition of signalling molecules
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“This novel binding mode seemed to confer desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitor”
BackgroundProbing the Probes: Fitness Factors For Small Molecule Tools
Workman, P., & Collins, I. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.05.013 · Cited by 300 · see citing works
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Identifying off-target effects and hidden phenotypes of drugs in human cells
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“EGCG is a potent and selective inhibitor of DYRK1A activity [22].”
Backgroundde la Torre, R., de Sola, S., Hernández, G., Farré, M., Pujol, J., Rodríguez, J. C., Espadaler, J. M., Langohr, K., Cuenca‐Royo, A., Príncipe, A., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30034-5 · Cited by 291 · see citing works
Formation of the head organizer in hydra involves the canonical Wnt pathway.
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“, 2000) but has no effect on GSK-3β (Bain et al., 2003).”
BackgroundMethodThe role of DYRK1A in neurodegenerative diseases
Węgiel, J., Gong, C., & Hwang, Y. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07955.x · Cited by 288 · see citing works
Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus
Ratz, P. H., Berg, K. M., Urban, N. H., & Miner, A. S. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00529.2004 · Cited by 287 · see citing works
“Y-27632 inhibits the tonic phase much more than the early phase of a KCl-induced contraction in rabbit femoral and renal arteries (202) and rat caudal artery (121), whereas 30 M ML-9, a MLC kinase and ROK inhibitor (15, 200), attenuates both early and tonic force (121).”
BackgroundRewired ERK-JNK Signaling Pathways in Melanoma
Lopez‐Bergami, P., Huang, C. C., Goydos, J. S., Yip, D., Bar‐Eli, M., Herlyn, M., Smalley, K. S. M., Mahale, A. M., Eroshkin, A. M., Aaronson, S. A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.03.009 · Cited by 287 · see citing works
“, 2000), it has been suggested that a structurally unrelated GSK3 inhibitor such as Kenpaullone should be used in combination with LiCl to confirm a GSK3 involvement (Bain et al., 2003).”
BackgroundThe JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer
Hammouda, M., Ford, A. E., Liu, Y., & Zhang, J. Y. (2020) · Cells · doi:10.3390/cells9040857 · Cited by 289 · see citing works
Hirota, T., Lewis, W. G., Liu, A. C., Lee, J. W., Schultz, P. G., & Kay, S. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811410106 · Cited by 283 · see citing works
“In contrast, roscovitine, that inhibits CDK but not GSK-3 (27), caused a long period phenotype (Table 1).”
BackgroundInfluentialHarmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation
Göckler, N., Jofré, G., Papadopoulos, C., Soppa, U., Tejedor, F., & Becker, W. (2009) · The FEBS Journal · doi:10.1111/j.1742-4658.2009.07346.x · Cited by 266 · see citing works
A reinvestigation of the multisite phosphorylation of the transcription factor c‐Jun
Morton, S., Davis, R. J., McLaren, A., & Cohen, P. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg388 · Cited by 281 · see citing works
Self-citationDevelopment of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A
Ogawa, Y., Nonaka, Y., Goto, T., Ohnishi, E., Hiramatsu, T., Kii, I., Yoshida, M., Ikura, T., Onogi, H., Shibuyà, H., et al. (2010) · Nature Communications · doi:10.1038/ncomms1090 · Cited by 276 · see citing works
“Other commonly used Dyrk1A inhibitors include roscovitine , purvalanol A and epigallocatechin gallate ( EGCG”
A review of connectivity map and computational approaches in pharmacogenomics
Musa, A., Ghoraie, L. S., Zhang, S., Galzko, G., Yli-Harja, O. P., Dehmer, M., Haibe‐Kains, B., & Emmert‐Streib, F. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbw112 · Cited by 275 · see citing works
“A GSK3B/ CDK2 inhibitor has shown a dose-dependent efficacy in inhibiting Ebola infection in vitro without causing cellular toxicity in human cell lines [67].”
BackgroundStructural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125
Heo, Y., Kim, S., Seo, C. I., Kim, Y. K., Sung, B., Lee, H. S., Lee, J. I., Park, S., Kim, J. H., Hwang, K. Y., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600212 · Cited by 275 · see citing works
“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 ).”
BackgroundResultInfluentialOverexpression of Dyrk1A contributes to neurofibrillary degeneration in down syndrome
Liu, F., Liang, Z., Wegiel, J., Hwang, Y., Iqbal, K., Grundke‐Iqbal, I., Ramakrishna, N., & Gong, C. (2008) · The FASEB Journal · doi:10.1096/fj.07-104539 · Cited by 272 · see citing works
“To verify the specificity of the assay, we added 10 M epigallocatechin-3-gallate (EGCG), a selective Dyrk1A inhibitor (22) into the assay mixture and found that EGCG inhibited 80% of the kinase activity in the brain extracts (Fig.”
MethodRybel, B. D., Audenaert, D., Vert, G., Rozhon, W., Mayerhofer, J., Peelman, F., Coutuer, S., Denayer, T., Jansen, L., Nguyen, L., et al. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.04.008 · Cited by 271 · see citing works
“basic protein (MBP), AURORA1 with histone H3, and of the human kinases as described previously (Bain et al., 2003; Demidov et al., 2005; Kiegerl et al., 2000).”
BackgroundA novel CDK5‐dependent pathway for regulating GSK3 activity and kinesin‐driven motility in neurons
Morfini, G. A., Szebenyi, G., Brown, H. J., Pant, H. C., Pigino, G. F., DeBoer, S. R., Beffert, U., & Brady, S. T. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600237 · Cited by 268 · see citing works
“In adipocytes or epithelial cells, GSK3 may be constitutively active (Ali et al, 2001), but increased GSK3 activity in neurons leads to neurite retraction (Munoz-Montano et al, 1999), apoptosis (Lucas et al, 2001), increased embryonic lethality (Hoeflich et al, 2000) and behavioral abnormalities…”
BackgroundDrugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic
Workman, P., Clarke, P. A., Raynaud, F. I., & van Montfort, R. L. M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4355 · Cited by 262 · see citing works
“In a recent update (16) of the earlier compendium (14, 15)”
Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., & Iwatsubo, T. (2007) · Biochemistry · doi:10.1021/bi061960m · Cited by 263 · see citing works
Contri, A., Brunati, A. M., Trentin, L., Cabrelle, A., Miorin, M., Cesaro, L., Pinna, L. A., Zambello, R., Semenzato, G., & Donella‐Deana, A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22094 · Cited by 260 · see citing works
“Accordingly, the combined use of these two inhibitors has been suggested for identifying the specific physiological roles of Src kinases (21).”
Gunn, W., Conley, A., Deininger, L., Olson, S. D., Prockop, D. J., & Gregory, C. A. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0220 · Cited by 260 · see citing works
Skov, S., Pedersen, M. T., Andresen, L. O., Straten, P. T., Woetmann, A., & Ødum, N. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0599 · Cited by 260 · see citing works
“By screening inhibitors of stress-related enzymes, we found that LiCl and kenpaullone, two structurally different inhibitors of GSK-3 kinase activity ( 38 ), potently inhibited FR901228-induced MICA/B expression in a concentration-dependent manner (Fig. 3A).”
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Assay of protein kinases using radiolabeled ATP: a protocol
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“In these assays, the reactions are done at room temperature and the [γ- 32 P]ATP is usually replaced by [γ- 33 P]ATP, as the latter isotope is a weaker β-emitter and thus has much less stringent requirements for shieldin”
BackgroundSelf-citationThe Jak/STAT pathway is involved in synaptic plasticity
Nicolas, C. S., Peineau, S., Amici, M., Csaba, Z., Fafouri, A., Javalet, C., Collett, V. J., Hildebrandt, L., Seaton, G., Choi, S.-L., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.024 · Cited by 246 · see citing works
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“A similar value was obtained with the standard synthetic peptide substrate for CK1 (Bain et al, 2003).”
MethodSelf-citationStructurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors
Feng, L., Geisselbrecht, Y., Blanck, S., Wilbuer, A., Atilla‐Gokcumen, G. E., Filippakopoulos, P., Kräling, K., Çelik, M. A., Harms, K., Maksimoska, J., et al. (2011) · Journal of the American Chemical Society · doi:10.1021/ja1112996 · Cited by 242 · see citing works
Preconditioning Doses of NMDA Promote Neuroprotection by Enhancing Neuronal Excitability
Soriano, F. X., Papadia, S., Hofmann, F., Hardingham, N. R., Bading, H., & Hardingham, G. E. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0455-06.2006 · Cited by 236 · see citing works
“Recent kinase inhibitor specificity studies led the authors to recommend the parallel use of LiCl and kenpaullone for identifying the role of GSK3β in physiological processes (Bain et al., 2003).”
Mayer, C., & Belsham, D. D. (2009) · Endocrinology · doi:10.1210/en.2009-1122 · Cited by 232 · see citing works
“a range of kinases and enzymes and at the concentration used should be selective for JNK, although it has been reported to inhibit other protein kinases in vitro (41, 42).”
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Cdk5 Phosphorylation of Doublecortin Ser297 Regulates Its Effect on Neuronal Migration
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Cell-Based Proteome Profiling of Potential Dasatinib Targets by Use of Affinity-Based Probes
Shi, H., Zhang, C., Chen, G. Y. J., & Yao, S. Q. (2012) · Journal of the American Chemical Society · doi:10.1021/ja208518u · Cited by 228 · see citing works
- 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
- Health Sciences › Medicine › Pathology and Forensic Medicine › 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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