Protein kinase inhibitor

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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.

Contents

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:

NameTargetCompanyClassFDA 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 antibody2006 Mar (SCCHN)
Cobimetinib MEK Exelixis / Genentech-Roche Small molecule2015 Nov (Advanced melanoma with BRAF mutation) in Combination with Vemurafenib (BRAF)
Crizotinib ALK/Met Pfizer Small molecule2011 Aug (NSCLC with Alk mutation)
Cabozantinib RET/MET/VEGFR2 Exelixis Small molecule2012 Nov (Metastatic medullary thyroid cancer)
Dacomitinib EGFR/ErbB2/ErbB4 Pfizer Small molecule 2018 Non-small cell lung cancer
Dasatinib multiple targets BMS Small molecule2006
Entrectinib TrkA/TrkB/TrkC/ROS1/ALK Ignyta Small moleculeOrphan Drug Designations (Neuroblastoma 12/14, Colorectal cancer, NSCLC, both 2/15)
Erdafitinib FGFR Janssen Small molecule2018 Breakthrough Therapy [5]
Erlotinib EGFR Genentech Small molecule2004
Fostamatinib Syk Rigel Pharmaceuticals / AstraZeneca Small moleculeNot yet [6]
Gefitinib EGFR AstraZeneca Small molecule2003 non-small cell lung cancer (NSCLC)
Ibrutinib BTK Pharmacyclics Small molecule2013
Imatinib Bcr-Abl Novartis Small molecule2001 (CML), 2002 (GIST) [7]
Lapatinib EGFR/ErbB2 GSK Small molecule2007 (HER2+ Breast)
Lenvatinib VEGFR2 Eisai Co. Small molecule2015 (thyroid), 2016 (renal)
Mubritinib  ? Takeda Small moleculeNot yet, possibly abandoned
Nilotinib Bcr-Abl Novartis Small molecule2007
Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline Small molecule2009 (RCC)
Pegaptanib VEGF OSI/ Pfizer RNA Aptamer 2004 (AMD)
Ruxolitinib JAK Incyte Small molecule2011 (Myelofibrosis)
Sorafenib multiple targets Onyx / Bayer Small molecule2005 Dec (kidney)
Sunitinib multiple targets SUGEN / Pfizer Small molecule2006 Jan (RCC & GIST)
SU6656 Src, others SUGEN Small moleculeNot approved
Tucatinib HER2 Seattle Genetics Small molecule2020
Vandetanib RET/VEGFR/EGFR AstraZeneca Small molecule2011
Vemurafenib BRAF Roche Small molecule2011 Aug (Advanced melanoma with BRAF mutation)

Comparison of available agents

Comparison of available agents used as Human Medicines
DrugSponsorTargetIndicationsMajor toxicitiesBlack box warning(s)MS
[Note 1] [8]
DFRPC (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-+++-CD12 July 201325 September 20137 November 2013
Aflibercept Bayer, Regeneron Pharmaceuticals VEGF Advanced colorectal cancer and wet macular degeneration.GI perforation, haemorrhage and hepatotoxicityNone+++/+++++/++-DC21 November 201122 November 20122 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 disturbancesNone++++-DD27 January 20123 September 201226 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++++/+-DC26 February 200412 January 200524 February 2005
Bosutinib Pfizer Bcr-Abl Second-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
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/AD29 November 2012N/AN/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++++++/+DD26 August 201123 October 201227 September 2013
Dacomitinib Pfizer ErbB family (irreversible)Advanced non-small cell lung cancer Diarrhea, rash, fatigue.NoneN/AN/AN/AN/AN/A27 September 20182 April 2019-
Dasatinib Bristol-Myers Squibb Bcr-Abl, Src, c-KIT Second-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
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-+++/++-CD18 November 200419 September 200530 January 2006
Gefitinib AstraZeneca, Teva EGFR Advanced non-small cell lung cancer with EGFR mutationHaemorrhage, 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-+++/++-CD5 May 2003 (discontinued)24 June 20097 September 2011
Imatinib Novartis Bcr-Abl First-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
Lapatinib GlaxoSmithKline HER2 HER2-positive advanced breast cancerHypersensitivity (rare), hepatotoxicity (uncommon), interstitial lung disease (uncommon) and cardiovascular problems.Hepatotoxicity-++-CD13 March 200710 June 200828 June 2007
Nilotinib Novartis Bcr-Abl Second-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
Panitumumab Amgen EGFR Colorectal cancer Electrolyte anomalies, anaphylaxis, blood clots, sepsis and pulmonary fibrosis.Dermatologic reactions and infusion reactions-++CC10 October 20063 December 200720 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-++-DD19 October 200914 June 201030 June 2010
Pegaptanib OSI, Pfizer VEGF Wet macular degeneration Hypertension, cataracts, haemorrhage, vitreous floater, transient ischaemic attack, retinal detachment, diabetes mellitus and urinary tract infectionNone-+/-++N/AB17 December 200431 January 2006N/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/AD14 December 20121 July 2013N/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---DC10 August 201222 January 200727 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+++/++++-DD27 September 201226 August 201329 November 2013
Ruxolitinib Novartis JAK Myelofibrosis Hypercholesterolaemia, urinary tract infection, herpes zoster, tuberculosis and hepatotoxicityNone+++--CC16 November 201123 August 20123 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++++-DD20 December 200519 July 200627 September 2006
Sunitinib Pfizer VEGFR, PDGFR Renal 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 [rare] and TEN [rare]), liver failure (uncommon) and pancreatitis (uncommon).Hepatotoxicity++++DD26 January 200619 July 200614 September 2006
Tofacitinib Pfizer JAK Rheumatoid arthritis Infections and malignanciesSerious infections and malignancies---N/AC6 November 2012N/A; refused 26 April 2013N/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-++B2D25 September 199828 August 200014 September 2000
Tucatinib Seattle Genetics HER2 Advanced unresectable or metastatic HER2-positive breast cancerDiarrhea, hepatotoxicity, embryo-fetal toxicityNoneApril 2020August 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 anomaliesQT interval prolongation-++-DD21 April 201117 February 201231 January 2013
Vemurafenib Roche BRAF Metastatic malignant melanoma Photosensitivity, 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.

  1. Myelosuppression.
  2. 1 2 PC = Pregnancy category

See also

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

<span class="mw-page-title-main">Dasatinib</span> Chemical compound

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.

<span class="mw-page-title-main">CD135</span> Protein-coding gene in the species Homo sapiens

Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3, receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in humans

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">Omacetaxine mepesuccinate</span> Chemical compound

Omacetaxine mepesuccinate is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase, the receptor of hepatocyte growth factor/scatter factor (HGF/SF). These inhibitors may have therapeutic application in the treatment of various types of cancers.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs used to treat several human diseases, including cancer, autoimmune diseases, and neurodegeneration. They function by inhibiting the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

<span class="mw-page-title-main">Osimertinib</span> Chemical compound, used as a medication to treat lung cancer

Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.

<span class="mw-page-title-main">Entrectinib</span> TKI inhibitor used for cancer treatment

Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

Craig M. Crews is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell. His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.

References

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  2. "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms". Archived from the original on 2008-05-11.
  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. S2CID   7817325.
  4. "Clinical trials using WEE1 inhibitor AZD1775". National Cancer Institute. Retrieved April 20, 2018.
  5. "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.
  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".
  8. "Medscape Multispecialty – Home page". WebMD . Retrieved 27 November 2013.[ full citation needed ]
  9. Monograph
  10. "European Public Assessment Reports". European Medicines Agency. Archived from the original on 4 February 2014. Retrieved 27 January 2014.[ full citation needed ]
  11. "Therapeutic Goods Administration – Home page". Department of Health (Australia) . Retrieved 27 November 2013.[ full citation needed ]

Further reading