Protein kinase inhibitor
A protein kinase inhibitor is a type of enzyme inhibitor that 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. Phosphate groups can turn a protein off.
The phosphate groups are usually added to the serine, threonine, or tyrosine amino acid on the protein. 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.
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.
Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation. The novel kinase inhibitor PLX5568 is currently in clinical trials for treatment of polycystic kidney disease as well as pain.
Currently there are several drugs launched or in development that target protein kinases and the receptors that activate them:
|Afatinib||EGFR/ErbB2||Boehringer Ingelheim||Small molecule||2013 Non-small cell lung cancer|
|Axitinib||VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-KIT||Pfizer||Small molecule||2012 Renal cell carcinoma|
|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|
|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|
|Pazopanib||VEGFR2/PDGFR/c-kit||GlaxoSmithKline||Small molecule||2009 (RCC)|
|Pegaptanib||VEGF||OSI/Pfizer||RNA Aptamer||2004 (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)|
|SU6656||multiple targets||SUGEN||Small molecule||2000 Jan (RCC & GIST)|
|Vandetanib||RET/VEGFR/EGFR||AstraZeneca||Small molecule||No, submission withdrawn Oct09 |
|Vemurafenib||BRAF||Roche||Small molecule||2011 Aug Melanoma|
Comparison of available agents
|Drug||Sponsor||Target||Indications||Major toxicities||Black box warning(s)|| MS
|D||FR|| PC (AU)
| PC (US)
|FDA AD||EMA AD||TGA AD|
|Afatinib||Boehringer Ingelheim||ErbB family (irreversible)||Advanced non-small cell lung cancer||Hepatotoxicity, kidney failure, electrolyte anomalies (mostly hypokalaemia) and interstitial lung disease (uncommon).||None||-||+++||-||C||D||12 July 2013||25 September 2013||7 November 2013|
|Aflibercept||Bayer, Regeneron||VEGF||Advanced colorectal cancer and wet macular degeneration.||GI perforation, haemorrhage and hepatotoxicity||None||+++/++||+++/++||-||D||C||21 November 2011||22 November 2012||2 April 2013|
|Axitinib||Pfizer||VEGFR, PDGFR, c-KIT||Renal cell carcinoma||Thyroid dysfunction, blood clots, haemorrhages, reversible posterior leucoencephalopathy syndrome (uncommon), GI perforation/fistula (uncommon) and electrolyte disturbances||None||++||++||-||D||D||27 January 2012||3 September 2012||26 July 2012|
|Bevacizumab||Genentech||VEGF||Colorectal cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, macular degeneration and glioblastoma||Hypertension, GI perforation, ovarian failure, GI haemorrhage, blood clots, electrolyte anomalies, ileus, congestive heart failure, osteonecrosis of the jaw (rare), necrotising fasciitis (rare), gallbladder perforation (rare)||GI perforation, haemorrhage and wound healing complications||++||++/+||-||D||C||26 February 2004||12 January 2005||24 February 2005|
|Bosutinib||Pfizer||Bcr-Abl||Second-line Chronic myelogenous leukaemia treatment||Lower respiratory tract infection, anaphylaxis (uncommon), electrolyte anomalies, cardiovascular effects (especially QT interval prolongation), GI haemorrhage (uncommon), hepatotoxicity and kidney failure.||None||++/+||+++||+||N/A||D||4 September 2012||27 March 2013||N/A|
|Cabozantinib||Exelixis||c-Met, VEGFR2||Metastatic thyroid cancer||Electrolyte anomalies, hypotension, peripheral sensory neuropathy, GI perforation/fistula, reversible posterior leucoencephalopathy syndrome (rare), blood clots and osteonecrosis.||GI haemorrhage, perforation and fistula||++||+++/++||-||N/A||D||29 November 2012||N/A||N/A|
|Crizotinib||Pfizer||ALK, HGFR, c-MET||Anaplastic lymphoma kinase-positive non-small cell lung cancer||Peripheral neuropathy, electrolyte anomalies, blood clots, kidney cyst, liver failure, interstitial lung disease and cardiotoxicity (probably QT interval prolongation).||None||++||++||++/+||D||D||26 August 2011||23 October 2012||27 September 2013|
|Dasatinib||Bristol-Myers Squibb||Bcr-Abl, Src, c-KIT||Second-line Chronic myelogenous leukaemia treatment||Electrolyte disturbances, haemorrhages, fluid retention, heart failure (uncommon), myocardial infarction (uncommon) and pulmonary hypertension||None||+/-||++||++||D||D||28 June 2006||20 November 2006||15 January 2007|
|Erlotinib||Roche||EGFR||Advanced non-small cell lung cancer and pancreatic cancer||GI bleeds (rare), liver failure (rare), hepatorenal syndrome (rare), EGFR skin reactions and interstitial lung disease(uncommon).||None||-||+++/++||-||C||D||18 November 2004||19 September 2005||30 January 2006|
|Gefitinib||AstraZeneca, Teva||EGFR||Advanced non-small cell lung cancer with EGFR mutation||Haemorrhage, EGFR skin reactions (including Stevens-Johnson syndrome [SJS; rare] and toxic epidermal necrolysis[TEN; rare]), liver failure (rare), hepatitis (uncommon), pancreatitis (uncommon) and interstitial lung disease (uncommon).||N/A||-||+++/++||-||C||D||5 May 2003 (discontinued)||24 June 2009||7 September 2011|
|Imatinib||Novartis||Bcr-Abl||First-line chronic myelogenous leukaemia treatment||Haemorrhage, electrolyte disturbances, cardiotoxicity (uncommon), kidney failure (uncommon), GI perforation, hepatotoxicity (rare) and rhabdomyolysis (rare)||N/A||+++/++||+||++||D||D||10 May 2001||7 November 2001||13 August 2001|
|Lapatinib||GlaxoSmithKline||HER2||HER2-positive advanced breast cancer||Hypersensitivity (rare), hepatotoxicity (uncommon), interstitial lung disease (uncommon) and cardiovascular problems.||Hepatotoxicity||-||++||-||C||D||13 March 2007||10 June 2008||28 June 2007|
|Nilotinib||Novartis||Bcr-Abl||Second-line chronic myelogenous leukaemia treatment||Hyperglycaemia, electrolyte disturbances, fluid retention, pancreatitis and cardiotoxicity (mostly QT interval prolongation).||QT interval prolongation and electrolyte anomalies||++||+||+||D||D||29 October 2007||2 June 2009||17 January 2008|
|Panitumumab||Amgen||EGFR||Colorectal cancer||Electrolyte anomalies, anaphylaxis, blood clots, sepsis and pulmonary fibrosis.||Dermatologic reactions and infusion reactions||-||+||+||C||C||10 October 2006||3 December 2007||20 March 2012|
|Pazopanib||GlaxoSmithKline||VEGFR, PDGFR, c-KIT||Renal cell carcinoma and soft tissue sarcoma||Cardiotoxicity (mostly QT interval prolongation but also heart failure [uncommon]), blood clots, haemorrhage, thyroid anomalies (mostly hypothyroidism), blood glucose anomalies (hypoglycaemia and hyperglycaemia), torsades de pointes (uncommon), hepatotoxicity (uncommon), GI perforation/fistula (uncommon) and reversible posterior leucoencephalopathy syndrome (rare).||Hepatotoxicity||-||++||-||D||D||19 October 2009||14 June 2010||30 June 2010|
|Pegaptanib||OSI, Pfizer||VEGF||Wet macular degeneration||Hypertension, cataracts, haemorrhage, vitreous floater, transient ischaemic attack, retinal detachment, diabetes mellitus and urinary tract infection||None||-||+/-||++||N/A||B||17 December 2004||31 January 2006||N/A|
|Ponatinib||ARIAD Pharmaceuticals||Bcr-Abl, BEGFR, PDGFR, FGFR, EPH, SRC, c-KIT, RET, TIE2, FLT3||T315I-positive Chronic myelogenous leukaemia and T315I-positive-Acute lymphoblastic leukaemia||Hypertension, pneumonia, urinary tract infection, sepsis, GI haemorrhage, liver failure, cardiovascular problems and blood clots.||Liver failure, blood clots and hepatotoxicity||++||+||+||N/A||D||14 December 2012||1 July 2013||N/A|
|Ranibizumab||Novartis||VEGF-A||Wet macular degeneration and macular oedema (including diabetic macular oedema)||Haemorrhage (conjunctival, vitreous and injection site), increased intraocular pressure, vitreous detachment and retinal degeneration.||None||-||-||-||D||C||10 August 2012||22 January 2007||27 February 2007|
|Regorafenib||Bayer||RET, VEGFR, PDGFR||Advanced colorectal cancer, gastrointestinal stromal tumours||Electrolyte anomalies, hepatotoxicity, hypotension, haemorrhage, GI fistula, thyroid problems and blood clots.||Hepatotoxicity||+++/++||++||-||D||D||27 September 2012||26 August 2013||29 November 2013|
|Ruxolitinib||Novartis||JAK||Myelofibrosis||Hypercholesterolaemia, urinary tract infection, herpes zoster, tuberculosis and hepatotoxicity||None||+++||-||-||C||C||16 November 2011||23 August 2012||3 July 2013|
|Sorafenib||Bayer||VEGFR, PDGFR, BRAF, c-KIT, etc.||Advanced Renal cell carcinoma and Hepatocellular carcinoma||Hypertension, peripheral neuropathy, thyroid dysfunction, cardiovascular problems (e.g. QT interval prolongation, heart attack or heart failure), electrolyte anomalies, GI perforation (uncommon), pancreatitis (uncommon), hepatitis (rare), nephrotic syndrome (rare) and reversible posterior leucoencephalopathy syndrome (rare)||None||++||++||-||D||D||20 December 2005||19 July 2006||27 September 2006|
|Sunitinib||Pfizer||VEGFR, PDGFR||Renal cell carcinoma, GI stromal tumour, pancreatic neuroendocrine tumour||Blood clots, cardiovascular problems (mostly heart failure or left ventricular dysfunction but also QT interval prolongation and torsades de pointes), thyroid dysfunction, electrolyte anomalies, skin reactions (including SJS [rare] and TEN [rare]), liver failure (uncommon) and pancreatitis (uncommon).||Hepatotoxicity||+||++||+||D||D||26 January 2006||19 July 2006||14 September 2006|
|Tofacitinib||Pfizer||JAK||Rheumatoid arthritis||Infections and malignancies||Serious infections and malignancies||-||-||-||N/A||C||6 November 2012||N/A; refused 26 April 2013||N/A|
|Trastuzumab||Genentech||HER2||Breast cancer (for either metastatic disease or adjuvant treatment), metastatic gastric cancer||Congestive heart failure, depression, pulmonary toxicity, infections and tachycardia (heart high rate)||Pulmonary toxicity, cardiomyopathy and a confusion warning||-||+||+||B2||D||25 September 1998||28 August 2000||14 September 2000|
|Vandetanib||AstraZeneca||VEGFR, EGFR, RET, BRK||Advanced medullary thyroid cancer||Urinary tract infection, hypertension, QT interval prolongation, electrolyte anomalies, depression, GI perforation and thyroid anomalies||QT interval prolongation||-||++||-||D||D||21 April 2011||17 February 2012||31 January 2013|
|Vemurafenib||Roche||BRAF||Metastatic malignant melanoma||Photosensitivity, squamous cell carcinoma and hepatotoxicity||None||-||+||+||D||D||17 August 2011||10 May 2012||17 February 2012|
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.
- PC = Pregnancy category
- PC = Pregnancy category
- "Plexxikon Initiates Phase 1 Trial for PLX5568".
- "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms".
- 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. PMID 19629074. doi:10.1038/nrd2871.
- Bajpai, M (2009). "Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases". IDrugs 12 (3): 174–85. PMID 19333898.
- "FDA Grants Imatinib (Gleevec) Full Approval for Adjuvant Treatment of GIST".
- "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.[full citation needed]
- "European Public Assessment Reports". European Medicines Agency. Retrieved 27 January 2014.[full citation needed]
- "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.[full citation needed]
- Protein kinase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
- IC50 values for common inhibitors
- "Table 1: Chemical structures and known kinase targets for clinically approved kinase inhibitors". in 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. PMID 19629074. doi:10.1038/nrd2871.