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.
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]
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) |
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.
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.
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.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
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.
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).
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.
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).
Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.
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.
Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.
Omacetaxine mepesuccinate, formerly named as homoharringtonine or HHT, 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, with 4 CDK4/6 inhibitors haven been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.
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.
Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK and ROS1 inhibitor.
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 are a class of drugs that inhibit 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.
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.
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.