protein kinase inhibitor 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. clinical use kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation. 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 there are several drugs launched or in development that target protein kinases and the receptors that activate them: nametargetcompanyclassfda approval adavosertibwee1astrazenecasmall moleculenot yet afatinibegfr/erbb2boehringer ingelheimsmall molecule2013 non-small cell lung cancer axitinibvegfr1/vegfr2/vegfr3/pdgfrb/c-kitpfizersmall molecule2012 renal cell carcinoma bosutinibbcr-abl / srcpfizersmall molecule2012 chronic myelogenous leukemia cetuximabegfrimclone / bmsmonoclonal antibody2006 mar (scchn) cobimetinibmekexelixis / genentech-rochesmall molecule2015 nov (advanced melanoma with braf mutation) in combination with vemurafenib (braf) crizotinibalk/metpfizersmall molecule2011 aug (nsclc with alk mutation) cabozantinibret/met/vegfr2exelixissmall molecule2012 nov (metastatic medullary thyroid cancer) dacomitinibegfr/erbb2/erbb4pfizersmall molecule2018 non-small cell lung cancer dasatinibmultiple targetsbmssmall molecule2006 entrectinibtrka/trkb/trkc/ros1/alkignytasmall moleculeorphan drug designations (neuroblastoma 12/14, colorectal cancer, nsclc, both 2/15) erdafitinibfgfrjanssensmall molecule2018 breakthrough therapy erlotinibegfrgenentechsmall molecule2004 fostamatinibsykrigel pharmaceuticals / astrazenecasmall moleculenot yet gefitinibegfrastrazenecasmall molecule2003 non-small cell lung cancer (nsclc) ibrutinibbtkpharmacyclicssmall molecule2013 imatinibbcr-ablnovartissmall molecule2001 (cml), 2002 (gist) lapatinibegfr/erbb2gsksmall molecule2007 (her2+ breast) lenvatinibvegfr2eisai co.small molecule2015 (thyroid), 2016 (renal) mubritinib ?takedasmall moleculenot yet, possibly abandoned nilotinibbcr-ablnovartissmall molecule2007 pazopanibvegfr2/pdgfr/c-kitglaxosmithklinesmall molecule2009 (rcc) pegaptanibvegfosi/ pfizerrna aptamer2004 (amd) ruxolitinibjakincytesmall molecule2011 (myelofibrosis) sorafenibmultiple targetsonyx / bayersmall molecule2005 dec (kidney) sunitinibmultiple targetssugen / pfizersmall molecule2006 jan (rcc & gist) su6656src, otherssugensmall moleculenot approved tucatinibher2seattle geneticssmall molecule2020 vandetanibret/vegfr/egfrastrazenecasmall molecule2011 vemurafenibbrafrochesmall molecule2011 aug (advanced melanoma with braf mutation) comparison of available agents comparison of available agents used as human medicines drugsponsortargetindicationsmajor toxicitiesblack box warning(s)msdfrpc (au)pc (us)fda adema adtga ad afatinibboehringer ingelheimerbb family (irreversible)advanced non-small cell lung cancerhepatotoxicity, kidney failure, electrolyte anomalies (mostly hypokalaemia) and interstitial lung disease (uncommon).none-+++-cd12 july 201325 september 20137 november 2013 afliberceptbayer, regeneron pharmaceuticalsvegfadvanced colorectal cancer and wet macular degeneration.gi perforation, haemorrhage and hepatotoxicitynone+++/+++++/++-dc21 november 201122 november 20122 april 2013 axitinibpfizervegfr, pdgfr, c-kitrenal cell carcinomathyroid dysfunction, blood clots, haemorrhages, reversible posterior leucoencephalopathy syndrome (uncommon), gi perforation/fistula (uncommon) and electrolyte disturbancesnone++++-dd27 january 20123 september 201226 july 2012 bevacizumabgenentechvegfcolorectal cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, macular degeneration and glioblastomahypertension, 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++++/+-dc26 february 200412 january 200524 february 2005 bosutinibpfizerbcr-ablsecond-line chronic myelogenous leukaemia treatmentlower respiratory tract infection, anaphylaxis (uncommon), electrolyte anomalies, cardiovascular effects (especially qt interval prolongation), gi haemorrhage (uncommon), hepatotoxicity and kidney failure.none++/+++++n/ad4 september 201227 march 2013n/a cabozantinibexelixisc-met, vegfr2metastatic thyroid cancerelectrolyte anomalies, hypotension, peripheral sensory neuropathy, gi perforation/fistula, reversible posterior leucoencephalopathy syndrome (rare), blood clots and osteonecrosis.gi haemorrhage, perforation and fistula+++++/++-n/ad29 november 2012n/an/a crizotinibpfizeralk, hgfr, c-metanaplastic lymphoma kinase-positive non-small cell lung cancerperipheral neuropathy, electrolyte anomalies, blood clots, kidney cyst, liver failure, interstitial lung disease and cardiotoxicity (probably qt interval prolongation).none++++++/+dd26 august 201123 october 201227 september 2013 dacomitinibpfizererbb family (irreversible)advanced non-small cell lung cancerdiarrhea, rash, fatigue.nonen/an/an/an/an/a27 september 20182 april 2019- dasatinibbristol-myers squibbbcr-abl, src, c-kitsecond-line chronic myelogenous leukaemia treatmentelectrolyte disturbances, haemorrhages, fluid retention, heart failure (uncommon), myocardial infarction (uncommon) and pulmonary hypertensionnone+/-++++dd28 june 200620 november 200615 january 2007 erlotinibrocheegfradvanced non-small cell lung cancer and pancreatic cancergi bleeds (rare), liver failure (rare), hepatorenal syndrome (rare), egfr skin reactions and interstitial lung disease(uncommon).none-+++/++-cd18 november 200419 september 200530 january 2006 gefitinibastrazeneca, tevaegfradvanced non-small cell lung cancer with egfr mutationhaemorrhage, egfr skin reactions (including stevens–johnson syndrome and toxic epidermal necrolysis), liver failure (rare), hepatitis (uncommon), pancreatitis (uncommon) and interstitial lung disease (uncommon).n/a-+++/++-cd5 may 2003 (discontinued)24 june 20097 september 2011 imatinibnovartisbcr-ablfirst-line chronic myelogenous leukaemia treatmenthaemorrhage, electrolyte disturbances, cardiotoxicity (uncommon), kidney failure (uncommon), gi perforation, hepatotoxicity (rare) and rhabdomyolysis (rare)n/a+++/+++++dd10 may 20017 november 200113 august 2001 lapatinibglaxosmithklineher2her2-positive advanced breast cancerhypersensitivity (rare), hepatotoxicity (uncommon), interstitial lung disease (uncommon) and cardiovascular problems.hepatotoxicity-++-cd13 march 200710 june 200828 june 2007 nilotinibnovartisbcr-ablsecond-line chronic myelogenous leukaemia treatmenthyperglycaemia, electrolyte disturbances, fluid retention, pancreatitis and cardiotoxicity (mostly qt interval prolongation).qt interval prolongation and electrolyte anomalies++++dd29 october 20072 june 200917 january 2008 panitumumabamgenegfrcolorectal cancerelectrolyte anomalies, anaphylaxis, blood clots, sepsis and pulmonary fibrosis.dermatologic reactions and infusion reactions-++cc10 october 20063 december 200720 march 2012 pazopanibglaxosmithklinevegfr, pdgfr, c-kitrenal cell carcinoma and soft tissue sarcomacardiotoxicity (mostly qt interval prolongation but also heart failure ), 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-++-dd19 october 200914 june 201030 june 2010 pegaptanibosi, pfizervegfwet macular degenerationhypertension, cataracts, haemorrhage, vitreous floater, transient ischaemic attack, retinal detachment, diabetes mellitus and urinary tract infectionnone-+/-++n/ab17 december 200431 january 2006n/a ponatinibariad pharmaceuticalsbcr-abl, begfr, pdgfr, fgfr, eph, src, c-kit, ret, tie2, flt3t315i-positive chronic myelogenous leukaemia and t315i-positive-acute lymphoblastic leukaemiahypertension, pneumonia, urinary tract infection, sepsis, gi haemorrhage, liver failure, cardiovascular problems and blood clots.liver failure, blood clots and hepatotoxicity++++n/ad14 december 20121 july 2013n/a ranibizumabnovartisvegf-awet macular degeneration and macular oedema (including diabetic macular oedema)haemorrhage (conjunctival, vitreous and injection site), increased intraocular pressure, vitreous detachment and retinal degeneration.none---dc10 august 201222 january 200727 february 2007 regorafenibbayerret, vegfr, pdgfradvanced colorectal cancer, gastrointestinal stromal tumourselectrolyte anomalies, hepatotoxicity, hypotension, haemorrhage, gi fistula, thyroid problems and blood clots.hepatotoxicity+++/++++-dd27 september 201226 august 201329 november 2013 ruxolitinibnovartisjakmyelofibrosishypercholesterolaemia, urinary tract infection, herpes zoster, tuberculosis and hepatotoxicitynone+++--cc16 november 201123 august 20123 july 2013 sorafenibbayervegfr, pdgfr, braf, c-kit, etc.advanced renal cell carcinoma and hepatocellular carcinomahypertension, 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++++-dd20 december 200519 july 200627 september 2006 sunitinibpfizervegfr, pdgfrrenal cell carcinoma, gi stromal tumour, pancreatic neuroendocrine tumourblood 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 and ten ), liver failure (uncommon) and pancreatitis (uncommon).hepatotoxicity++++dd26 january 200619 july 200614 september 2006 tofacitinibpfizerjakrheumatoid arthritisinfections and malignanciesserious infections and malignancies---n/ac6 november 2012n/a; refused 26 april 2013n/a trastuzumabgenentechher2breast cancer (for either metastatic disease or adjuvant treatment), metastatic gastric cancercongestive heart failure, depression, pulmonary toxicity, infections and tachycardia (heart high rate)pulmonary toxicity, cardiomyopathy and a confusion warning-++b2d25 september 199828 august 200014 september 2000 tucatinibseattle geneticsher2advanced unresectable or metastatic her2-positive breast cancerdiarrhea, hepatotoxicity, embryo-fetal toxicitynoneapril 2020august 2020 vandetanibastrazenecavegfr, egfr, ret, brkadvanced medullary thyroid cancerurinary tract infection, hypertension, qt interval prolongation, electrolyte anomalies, depression, gi perforation and thyroid anomaliesqt interval prolongation-++-dd21 april 201117 february 201231 january 2013 vemurafenibrochebrafmetastatic malignant melanomaphotosensitivity, squamous cell carcinoma and hepatotoxicitynone-++dd17 august 201110 may 201217 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. myelosuppression. pc = pregnancy category