Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec® (USA) or Glivec® (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is occasionally still referred to as CGP57148B or STI571 (especially in older publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ... When normal cells are damaged beyond repair, they are eliminated by apoptosis. ... Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland. ... World map showing Europe Europe is conventionally considered one of the seven continents which, in this case, is more a cultural and political distinction than a physiogeographic one. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ... In medical oncology, gastrointestinal stromal tumors (GIST) are a rare malignancy of the gastrointestinal tract (1-3% of all gastrointestinal malignancies). ... When normal cells are damaged or old they undergo apoptosis; cancer cells, however, avoid apoptosis. ...

It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of simply inhibiting rapidly dividing cells. Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation A tyrosine kinase (EC 2. ...

Molecular biology

Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK domain, leading to a decrease in activity. Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation A tyrosine kinase (EC 2. ... Ribbon diagram of the catalytically perfect enzyme TIM. An enzyme is a protein that catalyzes, or speeds up, a chemical reaction. ...

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor). In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. ... A karyotype showing translocation 9;22 Philadelphia chromosome or Philadelphia translocation is a specific genetic, chromosomal abnormality that is associated with chronic myelogenous leukemia (CML) and involves an exchange of material between chromosomes 9 and 22. ... Platelet-derived growth factor (PDGF) is one of the numerous proteins that regulate cell growth and division. ...

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, Imatinib is used to decrease bcr-abl activity. Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ... A karyotype showing translocation 9;22 Philadelphia chromosome or Philadelphia translocation is a specific genetic, chromosomal abnormality that is associated with chronic myelogenous leukemia (CML) and involves an exchange of material between chromosomes 9 and 22. ... Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation A tyrosine kinase (EC 2. ...

Imatinib works because p210bcr-abl requires a molecule of ATP to activate tyrosine residues on its substrates by phosphorylation. Imatinib instead docks in to this site and inhibits the protein competitively. Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above, but no known other tyrosine kinases. Imatinib does of course work on the abl protein of all cells but these have additional, normally redundant, pathways which allow the cell to continue to function normally even without this one. Tumour cells, however, have a dependence on bcr-abl (Deininger and Druker, 2003). Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions (Vigneri et al 2001). Mechanism of the drug imatinib. ... Adenosine 5-tripenis (ATP) is the nucleotide known in biochemistry as the molecular currency of intracellular energy transfer; that is, ATP is able to store and transport chemical energy within cells. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in cheese), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells to synthesize proteins. ... Phosphorylation is the addition of a phosphate (PO4) group to a protein or a small molecule. ... Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation A tyrosine kinase (EC 2. ... For other uses, see Cancer (disambiguation). ... Apoptosis In biology, apoptosis (from the Greek words apo = from and ptosis = falling, commonly pronounced ap-a-tow-sis[1]) is one of the main types of programmed cell death (PCD). ...

Uses

Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. Early clinical trials also show its potential for treatment of dermatofibrosarcoma protuberans. Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ... In medical oncology, gastrointestinal stromal tumors (GIST) are a rare malignancy of the gastrointestinal tract (1-3% of all gastrointestinal malignancies). ... When normal cells are damaged or old they undergo apoptosis; cancer cells, however, avoid apoptosis. ... Dermatofibrosarcoma protuberans (DFSP) is a rare neoplasm of the dermis layer of the skin, and is classified as a sarcoma. ...

In laboratory settings, imatinib is being used increasingly as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice with diabetes (Lassila 2004). Biochemistry laboratory at the University of Cologne. ... Platelet-derived growth factor (PDGF) is one of the numerous proteins that regulate cell growth and division. ... Feral mouse A mouse is a mammal that belongs to one of numerous species of small rodents in the genus Mus and various related genera of the family Muridæ (Old World Mice). ... Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels), especially after eating. ...

Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[1] Emory University is a private university in Atlanta, Georgia. ... Smallpox (also known by the Latin names Variola or Variola vera) is a highly contagious disease unique to humans. ...

Tolerance

bcr-abl kinase, which causes CML in green, inhibited by small molecule Imatinib mesylate in red, rendered with RasMol

In the United States, the Food and Drug Administration has approved imatinib as first-line treatment for CML (Deininger and Druker 2003). Imatinib has passed through Phase III trials for CML, and has been shown to be more effective than the previous standard treatment of α-interferon and cytarabine. Although the long-term side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated (eg. liver toxicity was much less than predicted). Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild. Image File history File links Download high resolution version (865x716, 75 KB)Crystal Structure Of The C-Abl Kinase Domain In Complex With Sti-571 ( Imatinib mesylate). ... Image File history File links Download high resolution version (865x716, 75 KB)Crystal Structure Of The C-Abl Kinase Domain In Complex With Sti-571 ( Imatinib mesylate). ... The term CML is an acronym which can refer to the following. ... Imatinib mesylate (or simply imatinib) is a new drug used to treat certain types of cancer. ... RasMol is a computer program written for molecular graphics visualization intended and used primarily for the depiction and exploration of biological macromolecule structures, such as those found in the Protein Data Bank. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Interferons (IFNs) are natural proteins produced by the cells of the immune systems of most animals in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. ... Cytarabine is a shortened form of cytosine arabinoside, a commonly used chemotherapy agent used mainly in the treatment of leukemia and non-Hodgkin lymphoma. ... Side-effect can mean: Side-effect (computer science), a state change caused by a function call Adverse drug reaction, an unintended consequence specifically arising from drug therapy Therapeutic effect (medicine), a desirable consequence of any kind of medical treatment, even though resulting as an unintended, unexpected consequence of the treatment... Edema (BE: oedema, formerly known as dropsy) is swelling of any organ or tissue due to accumulation of excess fluid. ... Nausea (Greek Ναυτεία) is the sensation of unease and discomfort in the stomach with an urge to vomit. ... RASH (Red and Anarchist Skinheads) is a left-wing anti-racist, anti-fascist skinhead group. ...

Metabolism

Metabolism of imatinib occurs in the liver and the main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile, only a small portion is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively. Basic piperazine structure Piperazine is a six-sided organic ring compound containing two opposing nitrogen atoms (see image). ... Half-Life For a quantity subject to exponential decay, the half-life is the time required for the quantity to fall to half of its initial value. ...

History

Imatinib was identified in the late 1990s by Dr Brian J. Druker for the pharmaceutical company Novartis as a potential agent for the use in CML. Its development is the template for rational drug design. Soon after identification of the bcr-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib (Druker and Lydon 2000). The 1990s decade refers to the years from 1990 to 1999, inclusive, the last decade of the 20th Century. ... A pharmaceutical company (or drug company) is a company licensed to discover, develop, market and distribute drugs. ... Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland. ... Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. ... Drug design is the approach of finding drugs by design, based on what the drug is targeting. ...

References

• Deininger M, Druker BJ. Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev 2003;55:401-423. PMID 12869662.
• Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. PMID 10619854.
• Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-42. PMID 14988091.
• Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001:7:228-234. PMID 11175855.

External link

• Patients' information website