Chemistry:Protein kinase inhibitor

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Short description: Enzymes that block actions of protein kinases

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.[citation needed]

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.[1]

Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases.[2] The effectiveness of kinase inhibitors on various cancers can vary from patient to patient.[3]

Examples

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

Name Target Company Class FDA approval
Adavosertib WEE1 AstraZeneca Small molecule Not yet[4]
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[5]
Erlotinib EGFR Genentech Small molecule 2004
Fostamatinib Syk Rigel Pharmaceuticals / AstraZeneca Small molecule Not yet[6]
Gefitinib EGFR AstraZeneca Small molecule 2003 non-small cell lung cancer (NSCLC)
Ibrutinib BTK Pharmacyclics Small molecule 2013
Imatinib Bcr-Abl Novartis Small molecule 2001 (CML), 2002 (GIST) [7]
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
Nilotinib Bcr-Abl Novartis Small molecule 2007
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
Vandetanib RET/VEGFR/EGFR AstraZeneca Small molecule 2011
Vemurafenib BRAF Roche Small molecule 2011 Aug (Advanced melanoma with BRAF mutation)

Comparison of available agents

Comparison of available agents used as Human Medicines
Drug Sponsor Target Indications Major toxicities Black box warning(s) MS
[Note 1][8]		 D FR PC (AU)
[Note 2]		 PC (US)
[Note 2]		 FDA AD[9] EMA AD[10] TGA AD[11]
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

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. ↑ 2.0 2.1 PC = Pregnancy category

See also

References

  1. ↑ "Targeting cancer with kinase inhibitors". The Journal of Clinical Investigation 125 (5): 1780–1789. May 2015. doi:10.1172/JCI76094. PMID 25932675. 
  2. ↑ "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms". http://www.cancer.gov/templates/db_alpha.aspx?CdrID=44833. 
  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. 
  4. ↑ "Clinical trials using WEE1 inhibitor AZD1775". https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/wee1-inhibitor-azd1775. 
  5. ↑ "Janssen announces U.S. FDA breakthrough therapy designation for erdafitinib in the Treatment of metastatic urothelial cancer". March 15, 2018. https://www.jnj.com/media-center/press-releases/janssen-announces-us-fda-breakthrough-therapy-designation-for-erdafitinib-in-the-treatment-of-metastatic-urothelial-cancer. 
  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". http://www.cancernetwork.com/gastrointestinal-stromal-tumor/content/article/10165/2028035. 
  8. ↑ "Medscape Multispecialty – Home page". WebMD. http://reference.medscape.com/medscapetoday. [full citation needed]
  9. ↑ Monograph
  10. ↑ "European Public Assessment Reports". European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d12. [full citation needed]
  11. ↑ "Therapeutic Goods Administration – Home page". Department of Health (Australia). https://www.ebs.tga.gov.au/. [full citation needed]

Further reading

External links



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