Protein kinase inhibitor

A protein kinase inhibitor is a type of enzyme inhibitor that specifically blocks the action of one or more protein kinases. Protein kinases are enzymes that add a phosphate (PO₄) group to a protein or other organic molecule, usually on the serine, threonine, or tyrosine amino acid. Hence, protein kinase inhibitors can be subdivided or characterised by the amino acids whose phosphorylation is inhibited: 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.^{[citation needed]}

Phosphorylation is a necessary step in some cancers and inflammatory diseases. Inhibiting the protein kinases, and therefore the phosphorylation, can treat these diseases. Therefore, protein kinase inhibitors are used as drugs.

Clinical use

Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation.^{[citation needed]} The novel kinase inhibitor PLX5568 is currently in clinical trials for treatment of polycystic kidney disease as well as pain.

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

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

Name	Target	Company	Class	FDA approval
Afatinib	EGFR/ErbB2	Boehringer Ingelheim	Small molecule	Not yet
Axitinib	VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-KIT	Pfizer	Small molecule	2012 Renal cell carcinoma
Bevacizumab	VEGF	Genentech	Monoclonal antibody	2004 Colorectal
Bosutinib	BcrAbl /SRC	Pfizer	Small molecule	2012 Chronic myelogenous leukemia
Cetuximab	ErbB1	Imclone/BMS	Monoclonal antibody	2006 Mar (SCCHN)
Crizotinib	ALK/Met	Pfizer	Small molecule	2011 Aug (NSCLC with Alk mutation)
Dasatinib	multiple targets	BMS	Small molecule	2006
Erlotinib	ErbB1	Genentech	Small molecule	2005 Nov ?
Fostamatinib	Syk	Rigel Pharmaceuticals/AstraZeneca	Small molecule	Not yet [1]
Gefitinib	EGFR	AstraZeneca	Small molecule	2003
Imatinib	Bcr-Abl	Novartis	Small molecule	2001 (CML), 2002 (GIST)
Lapatinib	ErbB1/ErbB2	GSK	Small molecule	2007 (HER2+ Breast)
Lenvatinib	VEGFR2/VEGFR2	Eisai Co.	Small molecule	Not yet
Mubritinib	?	Takeda	Small molecule	Not yet, possibly abandoned
Nilotinib	Bcr-Abl	Novartis	Small molecule	2007
Panitumumab	EGFR	Amgen	Monoclonal antibody	2006
Pazopanib	VEGFR2/PDGFR/c-kit	GlaxoSmithKline	Small molecule	2009 (RCC)
Pegaptanib	VEGF	OSI/Pfizer	RNA Aptamer	2004 (AMD)
Ranibizumab	VEGF	Genentech	Monoclonal antibody	2006 (AMD)
Ruxolitinib	JAK	Incyte	Small molecule	2011 (Myelofibrosis)
Sorafenib	multiple targets	Onyx/Bayer	Small molecule	2005 Dec (kidney)
Sunitinib	multiple targets	SUGEN/Pfizer	Small molecule	2006 Jan (RCC & GIST)
Trastuzumab	Erb2	Genentech	Monoclonal antibody	1998 (HER2+ breast cancer)
Vandetanib	RET/VEGFR/EGFR	AstraZeneca	Small molecule	No, submission withdrawn Oct09 [2]
Vemurafenib	BRAF	Roche	Small molecule	2011 Aug Melanoma

See also

• Tyrosine kinase inhibitor
• amino acid

External links

• Protein kinase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
• IC50 values for common inhibitors
• "Chemical structures and known kinase targets for clinically approved kinase inhibitors" Nature.com