A protein kinase inhibitor (PKI) is a type of

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its Enzyme activity, activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which Substrate (biochemistry), substrate molecules are converted ...

that blocks the action of one or more

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

s. Protein kinases are enzymes that

phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

(add a

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

, or PO₄, group) to a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

and can modulate its function. The phosphate groups are usually added to

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

, or

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s on the protein. Most kinases act on both serine and threonine, the

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

s 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 kinase Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are ho ...

s 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 Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. Some of the kinase inhibitors used in treating cancer are inhibitors of

s. 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.

References

External links

*
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 a

{{Chemotherapeutic agents

Clinical use

Examples

Comparison of available agents

See also

References

Further reading

External links