Protein kinases (E.C. 2.7.11.-) use the co-substrate ATP to phosphorylate serine and/or threonine residues on target proteins. Analysis of the human genome suggests the presence of 518 protein kinases in man (divided into 15 subfamilies), with over 100 protein kinase-like pseudogenes [2]. It is beyond the scope of the Concise Guide to list all these protein kinase activities, but full listings are available on the 'Detailed page' provided for each enzyme.

Most inhibitors of these enzymes have been assessed in cell-free investigations and so may appear to 'lose' potency and selectivity in intact cell assays. In particular, ambient ATP concentrations may be influential in responses to inhibitors, since the majority are directed at the ATP binding site [1] .

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* Key recommended reading is highlighted with an asterisk

Akritopoulou-Zanze I, Hajduk PJ. (2009) Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors. Drug Discov Today, 14 (5-6): 291-7. [PMID:19121409]

Arencibia JM, Pastor-Flores D, Bauer AF, Schulze JO, Biondi RM. (2013) AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Biochim Biophys Acta, 1834 (7): 1302-21. [PMID:23524293]

* Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB. (2021) Trends in kinase drug discovery: targets, indications and inhibitor design. Nature Reviews Drug Discovery,. DOI: 10.1038/s41573-021-00252-y

Bayascas JR. (2008) Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle, 7 (19): 2978-82. [PMID:18802401]

Borders AS, de Almeida L, Van Eldik LJ, Watterson DM. (2008) The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target. BMC Neurosci, 9 Suppl 2: S12. [PMID:19090985]

Boutros T, Chevet E, Metrakos P. (2008) Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev, 60 (3): 261-310. [PMID:18922965]

Breckler M, Berthouze M, Laurent AC, Crozatier B, Morel E, Lezoualc'h F. (2011) Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cell Signal, 23 (8): 1257-66. [PMID:21402149]

Brown MD, Sacks DB. (2009) Protein scaffolds in MAP kinase signalling. Cell Signal, 21 (4): 462-9. [PMID:19091303]

Carling D, Thornton C, Woods A, Sanders MJ. (2012) AMP-activated protein kinase: new regulation, new roles?. Biochem J, 445 (1): 11-27. [PMID:22702974]

Caunt CJ, Keyse SM. (2013) Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J, 280 (2): 489-504. [PMID:22812510]

Chène P. (2008) Challenges in design of biochemical assays for the identification of small molecules to target multiple conformations of protein kinases. Drug Discov Today, 13 (11-12): 522-9. [PMID:18549979]

Diviani D, Maric D, Pérez López I, Cavin S, Del Vescovo CD. (2013) A-kinase anchoring proteins: molecular regulators of the cardiac stress response. Biochim Biophys Acta, 1833 (4): 901-8. [PMID:22889610]

Duronio V. (2008) The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J, 415 (3): 333-44. [PMID:18842113]

Eglen R, Reisine T. (2011) Drug discovery and the human kinome: recent trends. Pharmacol Ther, 130 (2): 144-56. [PMID:21256157]

Goldstein DM, Gray NS, Zarrinkar PP. (2008) High-throughput kinase profiling as a platform for drug discovery. Nat Rev Drug Discov, 7 (5): 391-7. [PMID:18404149]

* Graves LM, Duncan JS, Whittle MC, Johnson GL. (2013) The dynamic nature of the kinome. Biochem J, 450 (1): 1-8. [PMID:23343193]

Gurevich EV, Tesmer JJ, Mushegian A, Gurevich VV. (2012) G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther, 133 (1): 40-69. [PMID:21903131]

Hardie DG, Ross FA, Hawley SA. (2012) AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol, 19 (10): 1222-36. [PMID:23102217]

Hardie DG, Ross FA, Hawley SA. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol, 13 (4): 251-62. [PMID:22436748]

Hofmann F, Bernhard D, Lukowski R, Weinmeister P. (2009) cGMP regulated protein kinases (cGK). Handb Exp Pharmacol, (191): 137-62. [PMID:19089329]

Johnson L. (2007) Protein kinases and their therapeutic exploitation. Biochem Soc Trans, 35 (Pt 1): 7-11. [PMID:17212579]

Kaliman P, Llagostera E. (2008) Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. Cell Signal, 20 (11): 1935-41. [PMID:18583094]

Kelly E, Bailey CP, Henderson G. (2008) Agonist-selective mechanisms of GPCR desensitization. Br J Pharmacol, 153 Suppl 1: S379-88. [PMID:18059321]

Kondoh K, Nishida E. (2007) Regulation of MAP kinases by MAP kinase phosphatases. Biochim Biophys Acta, 1773 (8): 1227-37. [PMID:17208316]

Krishna M, Narang H. (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci, 65 (22): 3525-44. [PMID:18668205]

LaFave LM, Levine RL. (2012) JAK2 the future: therapeutic strategies for JAK-dependent malignancies. Trends Pharmacol Sci, 33 (11): 574-82. [PMID:22995223]

Lang F, Strutz-Seebohm N, Seebohm G, Lang UE. (2010) Significance of SGK1 in the regulation of neuronal function. J Physiol (Lond.), 588 (Pt 18): 3349-54. [PMID:20530112]

Lawan A, Shi H, Gatzke F, Bennett AM. (2013) Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions. Cell Mol Life Sci, 70 (2): 223-37. [PMID:22695679]

Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, Osborne J, McGlynn K, Stippec S, Earnest S et al.. (2008) The roles of MAPKs in disease. Cell Res, 18 (4): 436-42. [PMID:18347614]

Liao JJ. (2007) Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem, 50 (3): 409-24. [PMID:17266192]

Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, Gray NS. (2013) Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol, 20 (2): 146-59. [PMID:23438744]

Ljubicic V, Jasmin BJ. (2013) AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends Mol Med, 19 (10): 614-24. [PMID:23891277]

Malemud CJ. (2007) Inhibitors of stress-activated protein/mitogen-activated protein kinase pathways. Curr Opin Pharmacol, 7 (3): 339-43. [PMID:17398158]

Manning BD, Cantley LC. (2007) AKT/PKB signaling: navigating downstream. Cell, 129 (7): 1261-74. [PMID:17604717]

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The Protein Kinase Complement of the Human Genome. Accessed on 09/02/2012. Modified on 09/02/2012. The Human Kinome, http://www.kinase.com/human/kinome/

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. (2002) The protein kinase complement of the human genome. Science, 298 (5600): 1912-34. [PMID:12471243]

* Martin KJ, Arthur JS. (2012) Selective kinase inhibitors as tools for neuroscience research. Neuropharmacology, 63 (7): 1227-37. [PMID:22846224]

May LT, Hill SJ. (2008) ERK phosphorylation: spatial and temporal regulation by G protein-coupled receptors. Int J Biochem Cell Biol, 40 (10): 2013-7. [PMID:18502166]

Meloche S, Pouysségur J. (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene, 26 (22): 3227-39. [PMID:17496918]

Menet CJ, Rompaey LV, Geney R. (2013) Advances in the discovery of selective JAK inhibitors. Prog Med Chem, 52: 153-223. [PMID:23384668]

Mochly-Rosen D, Das K, Grimes KV. (2012) Protein kinase C, an elusive therapeutic target?. Nat Rev Drug Discov, 11 (12): 937-57. [PMID:23197040]

Nithianandarajah-Jones GN, Wilm B, Goldring CE, Müller J, Cross MJ. (2012) ERK5: structure, regulation and function. Cell Signal, 24 (11): 2187-96. [PMID:22800864]

Pearce LR, Komander D, Alessi DR. (2010) The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol, 11 (1): 9-22. [PMID:20027184]

Premont RT, Gainetdinov RR. (2007) Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol, 69: 511-34. [PMID:17305472]

Prudent R, Cochet C. (2009) New protein kinase CK2 inhibitors: jumping out of the catalytic box. Chem Biol, 16 (2): 112-20. [PMID:19246001]

Roberts PJ, Der CJ. (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26 (22): 3291-310. [PMID:17496923]

Roskoski Jr R. (2012) MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun, 417 (1): 5-10. [PMID:22177953]

Rozengurt E. (2007) Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol, 213 (3): 589-602. [PMID:17786953]

Russo GL, Russo M, Ungaro P. (2013) AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochem Pharmacol, 86 (3): 339-50. [PMID:23747347]

* Saha D, Kharbanda A, Yan W, Lakkaniga NR, Frett B, Li HY. (2020) The Exploration of Chirality for Improved Druggability within the Human Kinome. J Med Chem, 63 (2): 441-469. [PMID:31550151]

Sale EM, Sale GJ. (2008) Protein kinase B: signalling roles and therapeutic targeting. Cell Mol Life Sci, 65 (1): 113-27. [PMID:17952368]

Scott JD, Dessauer CW, Taskén K. (2013) Creating order from chaos: cellular regulation by kinase anchoring. Annu Rev Pharmacol Toxicol, 53: 187-210. [PMID:23043438]

Sharma V, Wang Q, Lawrence DS. (2008) Peptide-based fluorescent sensors of protein kinase activity: design and applications. Biochim Biophys Acta, 1784 (1): 94-9. [PMID:17881302]

Shaul YD, Seger R. (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta, 1773 (8): 1213-26. [PMID:17112607]

Steinberg GR, Jørgensen SB. (2007) The AMP-activated protein kinase: role in regulation of skeletal muscle metabolism and insulin sensitivity. Mini Rev Med Chem, 7 (5): 519-26. [PMID:17504187]

Steinberg SF. (2012) Regulation of protein kinase D1 activity. Mol Pharmacol, 81 (3): 284-91. [PMID:22188925]

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Wagner EF, Nebreda AR. (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer, 9 (8): 537-49. [PMID:19629069]

Witczak CA, Sharoff CG, Goodyear LJ. (2008) AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci, 65 (23): 3737-55. [PMID:18810325]

Wu-Zhang AX, Newton AC. (2013) Protein kinase C pharmacology: refining the toolbox. Biochem J, 452 (2): 195-209. [PMID:23662807]

* Zarrin AA, Bao K, Lupardus P, Vucic D. (2021) Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov, 20 (1): 39-63. [PMID:33077936]

Zhang J, Yang PL, Gray NS. (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer, 9 (1): 28-39. [PMID:19104514]

Zhang Y, Dong C. (2007) Regulatory mechanisms of mitogen-activated kinase signaling. Cell Mol Life Sci, 64 (21): 2771-89. [PMID:17726577]

* Zhou Y, Yu H, Vind AC, Kong L, Liu Y, Song X, Tu Z, Yun C, Smaill JB, Zhang QW et al.. (2023) Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov). J Med Chem, 66 (11): 7405-7420. [PMID:37220641]

1. Davies SP, Reddy H, Caivano M, Cohen P. (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J, 351 (Pt 1): 95-105. [PMID:10998351]

2. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. (2002) The protein kinase complement of the human genome. Science, 298 (5600): 1912-34. [PMID:12471243]

Subcommittee members: Doriano Fabbro (Chairperson) PIQUR Therapeutics AG C1-27 Hochbergerstrasse 60C CH-4057 Basel Switzerland Elena Faccenda (Curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Deanery of Biomedical Sciences The University of Edinburgh Room 338 Hugh Robson Building George Square Edinburgh EH8 9XD UK David Gray Head of Biology Drug Discovery Unit University of Dundee Dundee DD1 5EH Peter Norman Norman Consulting 18 Pink Lane Burnham Bucks SL1 8JW UK