Tyrosine kinase inhibitor

Last updated
Crystal structure of the second generation Bcr-Abl tyrosine-kinase inhibitor nilotinib (red) in complex with an Abl kinase domain (blue). Nilotinib is used to treat chronic myelogenous leukemia (CML), a hematological malignancy. 3CS9 Abl1 Nilotinib.png
Crystal structure of the second generation Bcr-Abl tyrosine-kinase inhibitor nilotinib (red) in complex with an Abl kinase domain (blue). Nilotinib is used to treat chronic myelogenous leukemia (CML), a hematological malignancy.

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, but also for other diseases such as idiopathic pulmonary fibrosis. For example, they have substantially improved outcomes in chronic myelogenous leukemia.

Contents

They are also called tyrphostins, the short name for "tyrosine phosphorylation inhibitor", originally coined in a 1988 publication, [1] which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor (EGFR).

The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2. [2] [3]

Development of drugs

Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents. [4] [5] Based on this work imatinib was developed against chronic myelogenous leukemia (CML) [6] and later gefitinib and erlotinib aiming at the EGF receptor. Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for CML. [7]

Sunitinib, an inhibitor of the receptors for FGF, PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors. [8]

Adavosertib is a Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors. [9] However, toxicities such as myelosuppression, diarrhea, and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug. [10]

Lapatinib, FDA approved for treatment in conjunction with chemotherapy or hormone therapy, is also currently undergoing clinical trials in the treatment of HER2-overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing. A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea. [11]

Mechanisms

TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change. [12] Recently TKIs have been shown to deprive tyrosine kinases of access to the Cdc37-Hsp90 molecular chaperone system on which they depend for their cellular stability, leading to their ubiquitylation and degradation. [13] Signal transduction therapy can also be used for non-cancer proliferative diseases and for inflammatory conditions. [14] An example is nintedanib for the treatment of idiopathic pulmonary fibrosis. [15]

See also

Related Research Articles

Protein kinase 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 and the other 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.

Tyrosine kinase Class of enzymes that phosphorylate protein tyrosine residues

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.

Philadelphia chromosome Medical condition

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

Chronic myelogenous leukemia 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. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

Gefitinib Drug used in fighting breast, lung, and other cancers

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

Epidermal growth factor receptor Mammalian protein found in Homo sapiens

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.

Erlotinib

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

HER2/neu

Receptor tyrosine-protein kinase erbB-2, also known as CD340, proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 or HER2/neu.

Targeted 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.

Lapatinib

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 kinase

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.

Matuzumab is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed at the Wistar Institute in Philadelphia, Pennsylvania

Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma of the head and neck (SCCHN), a type of cancer.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2, Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

Alexander Levitzki

Alexander Levitzki is an Israeli biochemist who is a professor of biochemistry at the Hebrew University of Jerusalem.

ERBB3

Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.

Afatinib

Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

A431 cells are a model human cell line used in biomedical research.

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.

Growth factor receptor inhibitors are drugs that target the growth factor receptors of cells. They interfere with binding of the growth factor to the corresponding growth factor receptors, impeding cell growth and are used medically to treat cancer.

References

  1. ↑ Yaish P, Gazit A, Gilon C, Levitzki A (1988). "Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors". Science. 242 (4880): 933–935. Bibcode:1988Sci...242..933Y. doi:10.1126/science.3263702. PMID   3263702. S2CID   9593087.
  2. ↑ Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A (1991). "Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases". J Med Chem. 34 (6): 1896–907. doi:10.1021/jm00110a022. PMID   1676428.
  3. ↑ Osherov N, Gazit A, Gilon C, Levitzki A (1993). "Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins". J Biol Chem. 268 (15): 11134–42. PMID   8098709.
  4. ↑ Anafi M, Gazit A, Zehavi A, Ben-Neriah Y, Levitzki A (1993). "Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate". Blood. 82 (12): 3524–9. doi: 10.1182/blood.V82.12.3524.3524 . PMID   7505115.
  5. ↑ Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM (1996). "Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor". Nature. 379 (6566): 645–8. Bibcode:1996Natur.379..645M. doi:10.1038/379645a0. PMID   8628398. S2CID   2528506.
  6. ↑ Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat Med. 2 (5): 561–6. doi:10.1038/nm0596-561. PMID   8616716. S2CID   36102747.
  7. ↑ Rivera-Torres J, José ES (2019). "Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential". Frontiers in Pharmacology . 10: 1011. doi:10.3389/fphar.2019.01011. PMC   6759511 . PMID   31619990.
  8. ↑ Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996). "Flk-1 as a target for tumor growth inhibition". Cancer Res. 56 (15): 3540–5. PMID   8758924.
  9. ↑ "NCI drug dictionary adavosertib". National Cancer Dictionary. 2 February 2011. Retrieved April 20, 2018.
  10. ↑ Do K, et al. (October 2015). "Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors". Journal of Clinical Oncology. 33 (30): 3409–15. doi:10.1200/JCO.2014.60.4009. PMC   4606059 . PMID   25964244.
  11. ↑ Chien AJ, et al. (May 2014). "Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2–overexpressing breast cancer". Journal of Clinical Oncology. 32 (14): 1472–79. doi:10.1200/JCO.2013.52.1161. PMC   4017711 . PMID   24711549.
  12. ↑ Posner I, Engel M, Gazit A, Levitzki A (1994). "Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program". Mol. Pharmacol. 45 (4): 673–83. PMID   8183246.
  13. ↑ Polier; et al. (2013). "ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system". Nature Chemical Biology. 9 (5): 307–312. doi:10.1038/nchembio.1212. PMC   5695660 . PMID   23502424.
  14. ↑ Levitzki A, Mishani E (2006). "Tyrphostins and other tyrosine kinase inhibitors". Annu Rev Biochem. 75: 93–109. doi:10.1146/annurev.biochem.75.103004.142657. PMID   16756486.
  15. ↑ "Vargatef EPAR". European Medicines Agency (EMA). 20 January 2020.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.