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A protein kinase inhibitor (PKI) is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO₄, group) to a protein and can modulate its function.

The phosphate groups are usually added to serine, threonine, or tyrosine amino acids on the protein. Most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.

Phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases due to hyperactive protein kinases (including mutant or overexpressed kinases in cancer) or to modulate cell functions to overcome other disease drivers.

Clinical use

Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation.

Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases. The effectiveness of kinase inhibitors on various cancers can vary from patient to patient.

Examples

There are several drugs launched or in development that target protein kinases and the receptors that activate them:

Comparison of available agents

Note:
AD = Approval date.
MS = Myelosuppression.
D = Diarrhoea.
FR = Fluid retention.
As far as myelosuppression, diarrhoea and fluid retention goes: +++ means >70% of patients exhibit clinically significant myelosuppression. ++ means 30-70% of patients exhibit significant myelosuppression. + means 10-30% of patients exhibit significant myelosuppression. - means 0-10% of patients exhibit this side effect.
General references templates are given, which refer the reader to the respective drug database.

1. Myelosuppression.
2. ^ PC = Pregnancy category

See also

• Tyrosine kinase inhibitor

References

1. Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP (May 2015). "Targeting cancer with kinase inhibitors". The Journal of Clinical Investigation. 125 (5): 1780–1789. doi:10.1172/JCI76094. PMC 4463189. PMID 25932675.
2. "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms". Archived from the original on 2008-05-11.
3. Jänne, Pasi A.; Gray, Nathanael; Settleman, Jeff (2009). "Factors underlying sensitivity of cancers to small-molecule kinase inhibitors". Nature Reviews Drug Discovery. 8 (9): 709–23. doi:10.1038/nrd2871. PMID 19629074. S2CID 7817325.
4. "Clinical trials using WEE1 inhibitor AZD1775". National Cancer Institute. Retrieved April 20, 2018.
5. "Janssen announces U.S. FDA breakthrough therapy designation for erdafitinib in the Treatment of metastatic urothelial cancer". Johnson and Johnson. March 15, 2018. Retrieved April 20, 2018.
6. Bajpai, M (2009). "Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases". IDrugs. 12 (3): 174–85. PMID 19333898.
7. "FDA Grants Imatinib (Gleevec) Full Approval for Adjuvant Treatment of GIST".
8. "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.
9. Monograph
10. "European Public Assessment Reports". European Medicines Agency. Archived from the original on 4 February 2014. Retrieved 27 January 2014.
11. "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.

Further reading

• Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB (November 2021). "Trends in kinase drug discovery: targets, indications and inhibitor design". Nature Reviews. Drug Discovery. 20 (11): 839–861. doi:10.1038/s41573-021-00252-y. PMID 34354255. S2CID 236935403.
• Ayala-Aguilera CC, Valero T, Lorente-Macías Á, Baillache DJ, Croke S, Unciti-Broceta A (January 2022). "Small Molecule Kinase Inhibitor Drugs (1995-2021): Medical Indication, Pharmacology, and Synthesis" (PDF). Journal of Medicinal Chemistry. 65 (2): 1047–1131. doi:10.1021/acs.jmedchem.1c00963. PMID 34624192. S2CID 238528289.
• Carles F, Bourg S, Meyer C, Bonnet P (April 2018). "PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials". Molecules (Basel, Switzerland). 23 (4): 908. doi:10.3390/molecules23040908. PMC 6017449. PMID 29662024.
• Jänne PA, Gray N, Settleman J (September 2009). "Factors underlying sensitivity of cancers to small-molecule kinase inhibitors". Nature Reviews. Drug Discovery. 8 (9): 709–23. doi:10.1038/nrd2871. PMID 19629074. S2CID 7817325.
• Roskoski R (March 2021). "Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update". Pharmacological Research. 165: 105463. doi:10.1016/j.phrs.2021.105463. PMID 33513356. S2CID 231770008.

External links

• Protein+kinase+inhibitors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• PKIDB: A searchable database of kinase inhibitors in clinical trials containing physicochemical properties and structures, protein kinase targets, therapeutic indications, year of first approval, and trade names
• A list of US FDA-approved small molecule protein kinase inhibitors, their protein kinase targets, therapeutic indications, and links to the FDA label are provided at the Blue Ridge Institute for Medical Research web site.

• Protein kinase inhibitors