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 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.
There are several drugs launched or in development that target protein kinases and the receptors that activate them:
|Adavosertib||WEE1||AstraZeneca||Small molecule||Not yet|
|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||Bcr-Abl / SRC||Pfizer||Small molecule||2012 Chronic myelogenous leukemia|
|Cetuximab||EGFR||Imclone / BMS||Monoclonal antibody||2006 Mar (SCCHN)|
|Cobimetinib||MEK||Exelixis / Genentech-Roche||Small molecule||2015 Nov (Advanced melanoma with BRAF mutation) in Combination with Vemurafenib (BRAF)|
|Crizotinib||ALK/Met||Pfizer||Small molecule||2011 Aug (NSCLC with Alk mutation)|
|Cabozantinib||RET/MET/VEGFR2||Exelixis||Small molecule||2012 Nov (Metastatic medullary thyroid cancer)|
|Dacomitinib||EGFR/ErbB2/ErbB4||Pfizer||Small molecule||2018 Non-small cell lung cancer|
|Dasatinib||multiple targets||BMS||Small molecule||2006|
|Entrectinib||TrkA/TrkB/TrkC/ROS1/ALK||Ignyta||Small molecule||Orphan Drug Designations (Neuroblastoma 12/14, Colorectal cancer, NSCLC, both 2/15)|
|Erdafitinib||FGFR||Janssen||Small molecule||2018 Breakthrough Therapy|
|Fostamatinib||Syk||Rigel Pharmaceuticals / AstraZeneca||Small molecule||Not yet|
|Gefitinib||EGFR||AstraZeneca||Small molecule||2003 non-small cell lung cancer (NSCLC)|
|Imatinib||Bcr-Abl||Novartis||Small molecule||2001 (CML), 2002 (GIST) |
|Lapatinib||EGFR/ErbB2||GSK||Small molecule||2007 (HER2+ Breast)|
|Lenvatinib||VEGFR2||Eisai Co.||Small molecule||2015 (thyroid), 2016 (renal)|
|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||Src, others||SUGEN||Small molecule||Not approved|
|Tucatinib||HER2||Seattle Genetics||Small molecule||2020|
|Vemurafenib||BRAF||Roche||Small molecule||2011 Aug (Advanced melanoma with BRAF mutation)|
Comparison of available agents
|Drug||Sponsor||Target||Indications||Major toxicities||Black box warning(s)||MS
|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 Pharmaceuticals||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|
|Dacomitinib||Pfizer||ErbB family (irreversible)||Advanced non-small cell lung cancer||Diarrhea, rash, fatigue.||None||N/A||N/A||N/A||N/A||N/A||27 September 2018||2 April 2019||-|
|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|
|Tucatinib||Seattle Genetics||HER2||Advanced unresectable or metastatic HER2-positive breast cancer||Diarrhea, hepatotoxicity, embryo-fetal toxicity||None||April 2020||August 2020|
|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
- Gross, Stefan; Rahal, Rami; Stransky, Nicolas; Lengauer, Christoph; Hoeflich, Klaus P. (1 May 2015). "Targeting cancer with kinase inhibitors". The Journal of Clinical Investigation. 125 (5): 1780–1789. doi:10.1172/JCI76094. ISSN 0021-9738. PMC 4463189. PMID 25932675.
- jula, MAYA (2015). "System Development". PubMed.gov. Vol. 125, no. 5. pp. 1780–1789. doi:10.1172/JCI76094. PMC 4463189. PMID 25932675.
- "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms". Archived from the original on 2008-05-11.
- 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.
- "Clinical trials using WEE1 inhibitor AZD1775". National Cancer Institute. Retrieved April 20, 2018.
- "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.
- 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]
- Ayala-Aguilera, C. C.; Valero, T.; Lorente-Macías, Á.; Baillache, D. J.; Croke, S.; Unciti-Broceta, A. Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis. J. Med. Chem. 2021.
- 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 *Carles, F; Bourg, S; Meyer, C; Bonnet, P (2018). "PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials". Molecules. 23 (4): 908. doi:10.3390/molecules23040908. PMC 6017449. PMID 29662024.
- Protein+kinase+inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
- IC50 values for common inhibitors
- Jänne, PA; Gray, N; Settleman, J (September 2009). "Table 1: Chemical structures and known kinase targets for clinically approved kinase inhibitors". Nat Rev Drug Discov. 8 (9): 709–23. doi:10.1038/nrd2871. PMID 19629074. S2CID 7817325. 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. doi:10.1038/nrd2871. PMID 19629074. S2CID 7817325.
- Attwood, Misty M; Fabbro, Doriano; Sokolov, Aleksandr V; Knapp, Stephan;, Schiöth, Helgi B. (2021) Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. doi: 10.1038/s41573-021-00252-y. PMID 34354255
- 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. Roskoski, R. Jr. (2021) Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update. Pharmacol Res.165:105463. doi:10.1016/j.phrs.2021.105463. PMID 33513356