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Wikipedia

Imatinib

January 17, 2023

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer.[2] Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β.[3][4] Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome-positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.[2]

Imatinib
Clinical data
Trade namesGleevec, Glivec, others
Other namesSTI-571
AHFS/Drugs.comMonograph
MedlinePlusa606018
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classTyrosine kinase inhibitor[2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability98%
Protein binding95%
Metabolismliver (mainly CYP3A4-mediated)
Elimination half-life18 h (imatinib)
40 h (active metabolite)
ExcretionFecal (68%) and kidney (13%)
Identifiers
  • 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide
CAS Number
  • 152459-95-5 Y
    220127-57-1 (mesilate)
PubChem CID
  • 5291
IUPHAR/BPS
  • 5687
DrugBank
  • DB00619 Y
ChemSpider
  • 5101 Y
UNII
  • BKJ8M8G5HI
KEGG
  • D08066 Y
ChEBI
  • CHEBI:45783 Y
ChEMBL
  • ChEMBL941 Y
PDB ligand
  • STI (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID3037125
ECHA InfoCard100.122.739
Chemical and physical data
FormulaC29H31N7O
Molar mass493.615 g·mol−1
3D model (JSmol)
  • Interactive image
  • Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)NC(=O)c4ccc(cc4)CN5CCN(CC5)C
  • InChI=1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34) Y
  • Key:KTUFNOKKBVMGRW-UHFFFAOYSA-N Y
  (verify)

Common side effects include vomiting, diarrhea, muscle pain, headache, and rash.[2] Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure.[2] Use during pregnancy may result in harm to the baby.[2] Imatinib works by stopping the Bcr-Abl tyrosine-kinase.[2] This can slow growth or result in programmed cell death of certain types of cancer cells.[2]

Imatinib was approved for medical use in the United States in 2001.[2] It is on the World Health Organization's List of Essential Medicines.[5] A generic version became available in the UK as of 2017.[6]

Medical uses

Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. In 2006 the FDA expanded approved use to include dermatofibrosarcoma protuberans (DFSP), myelodysplastic/myeloproliferative diseases (MDS/MPD), and aggressive systemic mastocytosis (ASM).[7]

Chronic myelogenous leukemia

The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple contexts of Philadelphia chromosome-positive CML, including after stem cell transplant, in blast crisis, and newly diagnosed.[8]

Due in part to the development of imatinib and related drugs, the five-year survival rate for people with chronic myeloid leukemia increased from 31% in 1993, to 59% in 2009,[9] to 70% in 2016.[10] Starting from 2011, it became clear that CML patients who continue to respond to imatinib have the same or almost the same life expectancy as the general population.[11]

Gastrointestinal stromal tumors

The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.[12] The drug is also approved in unresectable KIT-positive GISTs.[8]

Dermatofibrosarcoma protuberans (DFSP)

The FDA granted approval for the treatment of dermatofibrosarcoma protuberans (DFSP) patients in 2006.[7] Specifically adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). Prior to approval DFSP was considered unresponsive to chemotherapy treatments.

Other

The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.[8] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.[13]

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.[14][15][16][17] According to a small trial, imatinib is an effective drug in some patients with aggressive fibromatosis.[18]

Contraindications and cautions

The only known contraindication to imatinib is hypersensitivity to imatinib.[19] Cautions include:[20]

  • Hepatic impairment
  • Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities
  • Pregnancy, risk of embryo-fetal toxicity
  • Risk of fluid retention
  • Risk of growth stunting in children or adolescents

Side effects

 
bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).

The most common side effects include nausea, vomiting, diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite;[21] weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema.[22] Although rare, restoration of hair color has been reported as well.[23][24] Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.[25]

If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.[26]

Overdose

Medical experience with imatinib overdose is limited.[27] Treatment is supportive.[27] Imatinib is highly plasma protein-bound:[27] dialysis is unlikely to be helpful removing imatinib.

Interactions

Its use is advised against in people on strong CYP3A4 inhibitors such as clarithromycin, chloramphenicol, ketoconazole, ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism.[20] Likewise it is a CYP3A4, CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs.[20] Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.[22]

As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.[28]

Pharmacology

Mechanism of action

 
Imatinib
Drug mechanism
 
Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).[29]
Therapeutic usechronic myelogenous leukemia
Biological targetABL, c-kit, PDGF-R
Mechanism of actionTyrosine-kinase inhibitor
External links
ATC codeL01XE01
PDB ligand idSTI: PDBe, RCSB PDB
LIGPLOT1iep

Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

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 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 constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[30] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[31]

Imatinib is quite selective for bcr-abl, though it does also inhibit other targets mentioned above (c-kit and PDGF-R), as well as ABL2 (ARG) and DDR1 tyrosine kinases and NQO2 – an oxidoreductase.[32] Imatinib also inhibits the abl protein of non-cancer cells, but these cells normally have additional redundant tyrosine kinases, which allows them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[33] 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, leading to tumor cell death.[34]

Other pathways affected

The Bcr-Abl pathway has many downstream pathways including[35]

  • the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth.
  • It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion.
  • The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival.
  • The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.[35]

Pharmacokinetics

Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug 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 h and 40 h, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.[36]

Chemistry

Synthesis

 

History

Imatinib was invented in the late 1990s by scientists at Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis), in a team led by the British biochemist Nicholas Lydon and that included Elisabeth Buchdunger and Jürg Zimmermann,[37] and its use to treat CML was driven by oncologist Brian Druker of Oregon Health & Science University (OHSU).[38] Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician, scientist, and hematologist at the University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, and later on by Charles Sawyers of Memorial Sloan Kettering Cancer Center in New York.[38][39]

Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 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.[40]

When Novartis tested imatinib in rats, mice, rabbits, dogs, and monkeys in 1996, it was found to have several toxic effects; in particular, results indicating liver damage in dogs nearly stopped drug development completely. However, favorable results in studies with monkeys and in vitro human cells allowed testing to continue in humans.[41][42][43]

The first clinical trial of Gleevec took place in 1998, after Novartis reluctantly synthesized and released a few grams of the drug for Druker, enough for him to run a trial using a hundred or so patients.[44] The drug received FDA approval in May 2001, only two and a half years after the new drug application was submitted.[37][45] On the same month it made the cover of TIME magazine as a "bullet" to be used against cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[38]

During the FDA review, the tradename of the drug for the US market was changed from "Glivec" to "Gleevec" at the request of the FDA, to avoid confusion with Glyset, a diabetes drug.[46][47][48]

A Swiss patent application was filed on imatinib and various salts on in April 1992, which was then filed in the EU, the US, and other countries in March and April 1993.[49][50] and in 1996 United States and European patent offices issued patents listing Jürg Zimmermann as the inventor.[49][51]

In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate (the mesylate salt of imatinib). The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form.[52]: 3 and 4  In 1998, Novartis filed international patent applications claiming priority to the 1997 filing.[53][54] A United States patent was granted in 2005.[55]

Society and culture

Economics

 
A box of 400-milligram Glivec tablets (Novartis), as sold in Germany.

In 2013, more than 100 cancer specialists published a letter in Blood saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States couldn't afford them, and that the level of prices, and profits, was so high as to be immoral. Signatories of the letter included Brian Druker, Carlo Gambacorti-Passerini, and John Goldman, developers of imatinib.[56][57] They wrote that in 2001, imatinib was priced at $30,000 (equivalent to $45,911 in 2021) a year, which was based on the price of interferon, then the standard treatment, and that at this price Novartis would have recouped its initial development costs in two years. They wrote that after unexpectedly becoming a blockbuster, Novartis increased the price to $92,000 (equivalent to $108,589 in 2021) per year in 2012, with annual revenues of $4.7 billion. Other physicians have complained about the cost.[58][59][60]

Druker, who led the clinical studies, never received any royalties or profits from the success of the drug.[61]

By 2016, the average wholesale price had increased to $120,000 (equivalent to $135,491 in 2021) a year, according to an analysis prepared for The Washington Post by Stacie Dusetzina of the University of North Carolina at Chapel Hill. When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population,[clarification needed] and Novartis raised the price of Gleevec to match them.[62]

A 2012 economic analysis funded by Bristol-Myers Squibb estimated that the discovery and development of imatinib and related drugs had created $143 billion in societal value at a cost to consumers of approximately $14 billion. The $143 billion figure was based on an estimated 7.5 to 17.5 year survival advantage conferred by imatinib treatment, and included the value (discounted at 3% per annum) of ongoing benefits to society after the imatinib patent expiration.[63]

Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,[64] although generic imatinib is cheaper, as low as $2 per pill.[65]

Controversies

Patent litigation in India

Main article: Novartis v. Union of India & Others

Novartis fought a seven-year, controversial battle to patent Gleevec in India, and took the case all the way to the Indian Supreme Court. The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect.[66][67]

The patent application[54][68] claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate).[69]: 3  In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts vaguely specified, in many countries but could not patent it in India.[49][51] The key differences between the two patent applications, were that 1998 patent application specified the counterion (Gleevec is a specific salt – imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec – the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) – while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.[70]

As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.[71] Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.[72][73]

When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy."[72][74] At one point, Novartis went to court to try to invalidate Section 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal.[75] Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.

The Supreme Court case hinged on the interpretation of Section 3d. The Supreme Court issued its decision in 2013, ruling that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.[76]

Research

One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT.[77] However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.

Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension. It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.[78] However, a long-term trial of Imatinib in people with pulmonary arterial hypertension was unsuccessful, and serious and unexpected adverse events were frequent. These included 6 subdural hematomas and 17 deaths during or within 30 days of study end.[79]

In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used 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 without[80] or with diabetes.[81]

Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[82]

In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP). GSAP selectively increases the production and accumulation of neurotoxic beta-amyloid plaques, which suggests that molecules which target GSAP and are able to cross blood–brain barrier are potential therapeutic agents for treating Alzheimer's disease.[83] Another study suggests that imatinib may not need to cross the blood–brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain.[84] It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.[85]

A formulation of imatinib with a cyclodextrin (Captisol) as a carrier to overcome the blood–brain barrier has shown reversal of opioid tolerance in a 2012 study in rats.[86] Imatinib is an experimental drug in the treatment of desmoid tumor or aggressive fibromatosis.[medical citation needed]

Etymology

The -tinib word stem makes reference to the drug's action as a tyrosine kinase (TYK) inhibitor.[87]

See also

References

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External links

  • "Imatinib". Drug Information Portal. U.S. National Library of Medicine.
  • "Imatinib mesylate". Drug Information Portal. U.S. National Library of Medicine.
  • "Imatinib mesylate". National Cancer Institute. 5 October 2006.

January 17, 2023
imatinib, sold, under, brand, names, gleevec, glivec, both, marketed, worldwide, novartis, among, others, oral, chemotherapy, medication, used, treat, cancer, small, molecule, inhibitor, targeting, multiple, receptor, tyrosine, kinases, such, csf1r, flt3, pdgf. Imatinib sold under the brand names Gleevec and Glivec both marketed worldwide by Novartis among others is an oral chemotherapy medication used to treat cancer 2 Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kinases such as CSF1R ABL c KIT FLT3 and PDGFR b 3 4 Specifically it is used for chronic myelogenous leukemia CML and acute lymphocytic leukemia ALL that are Philadelphia chromosome positive Ph certain types of gastrointestinal stromal tumors GIST hypereosinophilic syndrome HES chronic eosinophilic leukemia CEL systemic mastocytosis and myelodysplastic syndrome 2 ImatinibClinical dataTrade namesGleevec Glivec othersOther namesSTI 571AHFS Drugs comMonographMedlinePlusa606018License dataEU EMA by INN US DailyMed Imatinib US FDA ImatinibPregnancycategoryAU D 1 Routes ofadministrationBy mouthDrug classTyrosine kinase inhibitor 2 ATC codeL01EA01 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US only EU Rx onlyPharmacokinetic dataBioavailability98 Protein binding95 Metabolismliver mainly CYP3A4 mediated Elimination half life18 h imatinib 40 h active metabolite ExcretionFecal 68 and kidney 13 IdentifiersIUPAC name 4 4 methylpiperazin 1 yl methyl N 4 methyl 3 4 pyridin 3 yl pyrimidin 2 yl amino phenyl benzamideCAS Number152459 95 5 Y 220127 57 1 mesilate PubChem CID5291IUPHAR BPS5687DrugBankDB00619 YChemSpider5101 YUNIIBKJ8M8G5HIKEGGD08066 YChEBICHEBI 45783 YChEMBLChEMBL941 YPDB ligandSTI PDBe RCSB PDB CompTox Dashboard EPA DTXSID3037125ECHA InfoCard100 122 739Chemical and physical dataFormulaC 29H 31N 7OMolar mass493 615 g mol 13D model JSmol Interactive imageSMILES Cc1ccc cc1Nc2nccc n2 c3cccnc3 NC O c4ccc cc4 CN5CCN CC5 CInChI InChI 1S C29H31N7O c1 21 5 10 25 18 27 21 34 29 31 13 11 26 33 29 24 4 3 12 30 19 24 32 28 37 23 8 6 22 7 9 23 20 36 16 14 35 2 15 17 36 h3 13 18 19H 14 17 20H2 1 2H3 H 32 37 H 31 33 34 YKey KTUFNOKKBVMGRW UHFFFAOYSA N Y verify Common side effects include vomiting diarrhea muscle pain headache and rash 2 Severe side effects may include fluid retention gastrointestinal bleeding bone marrow suppression liver problems and heart failure 2 Use during pregnancy may result in harm to the baby 2 Imatinib works by stopping the Bcr Abl tyrosine kinase 2 This can slow growth or result in programmed cell death of certain types of cancer cells 2 Imatinib was approved for medical use in the United States in 2001 2 It is on the World Health Organization s List of Essential Medicines 5 A generic version became available in the UK as of 2017 6 Contents 1 Medical uses 1 1 Chronic myelogenous leukemia 1 2 Gastrointestinal stromal tumors 1 3 Dermatofibrosarcoma protuberans DFSP 1 4 Other 2 Contraindications and cautions 3 Side effects 4 Overdose 5 Interactions 6 Pharmacology 6 1 Mechanism of action 6 1 1 Other pathways affected 6 2 Pharmacokinetics 7 Chemistry 7 1 Synthesis 8 History 9 Society and culture 9 1 Economics 9 2 Controversies 9 2 1 Patent litigation in India 10 Research 11 Etymology 12 See also 13 References 14 External linksMedical uses EditImatinib is used to treat chronic myelogenous leukemia CML gastrointestinal stromal tumors GISTs and a number of other malignancies In 2006 the FDA expanded approved use to include dermatofibrosarcoma protuberans DFSP myelodysplastic myeloproliferative diseases MDS MPD and aggressive systemic mastocytosis ASM 7 Chronic myelogenous leukemia Edit The U S Food and Drug Administration FDA has approved imatinib as first line treatment for Philadelphia chromosome positive CML both in adults and children The drug is approved in multiple contexts of Philadelphia chromosome positive CML including after stem cell transplant in blast crisis and newly diagnosed 8 Due in part to the development of imatinib and related drugs the five year survival rate for people with chronic myeloid leukemia increased from 31 in 1993 to 59 in 2009 9 to 70 in 2016 10 Starting from 2011 it became clear that CML patients who continue to respond to imatinib have the same or almost the same life expectancy as the general population 11 Gastrointestinal stromal tumors Edit The FDA first granted approval for advanced GIST patients in 2002 On 1 February 2012 imatinib was approved for use after the surgical removal of KIT positive tumors to help prevent recurrence 12 The drug is also approved in unresectable KIT positive GISTs 8 Dermatofibrosarcoma protuberans DFSP Edit The FDA granted approval for the treatment of dermatofibrosarcoma protuberans DFSP patients in 2006 7 Specifically adult patients with unresectable recurrent and or metastatic dermatofibrosarcoma protuberans DFSP Prior to approval DFSP was considered unresponsive to chemotherapy treatments Other Edit The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia Ph ALL myelodysplastic myeloproliferative diseases associated with platelet derived growth factor receptor gene rearrangements aggressive systemic mastocytosis without or an unknown D816V c KIT mutation hypereosinophilic syndrome and or chronic eosinophilic leukemia who have the FIP1L1 PDGFRa fusion kinase CHIC2 allele deletion or FIP1L1 PDGFRa fusion kinase negative or unknown unresectable recurrent and or metastatic dermatofibrosarcoma protuberans 8 On 25 January 2013 Gleevec was approved for use in children with Ph ALL 13 For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I early research has shown potential for using the c KIT tyrosine kinase blocking properties of imatinib 14 15 16 17 According to a small trial imatinib is an effective drug in some patients with aggressive fibromatosis 18 Contraindications and cautions EditThe only known contraindication to imatinib is hypersensitivity to imatinib 19 Cautions include 20 Hepatic impairment Risk of severe CHF or left ventricular dysfunction especially in patients with comorbidities Pregnancy risk of embryo fetal toxicity Risk of fluid retention Risk of growth stunting in children or adolescentsSide effects Edit bcr abl kinase green which causes CML inhibited by imatinib red small molecule The most common side effects include nausea vomiting diarrhea headaches leg aches cramps fluid retention visual disturbances itchy rash lowered resistance to infection bruising or bleeding loss of appetite 21 weight gain reduced number of blood cells neutropenia thrombocytopenia anemia and edema 22 Although rare restoration of hair color has been reported as well 23 24 Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium 25 If imatinib is used in prepubescent children it can delay normal growth although a proportion will experience catch up growth during puberty 26 Overdose EditMedical experience with imatinib overdose is limited 27 Treatment is supportive 27 Imatinib is highly plasma protein bound 27 dialysis is unlikely to be helpful removing imatinib Interactions EditIts use is advised against in people on strong CYP3A4 inhibitors such as clarithromycin chloramphenicol ketoconazole ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism 20 Likewise it is a CYP3A4 CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs 20 Since imatinib is mainly metabolised via the liver enzyme CYP3A4 substances influencing the activity of this enzyme change the plasma concentration of the drug An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole The same could be true of itraconazole clarithromycin grapefruit juice among others Conversely CYP3A4 inductors like rifampicin and St John s Wort reduce the drug s activity risking therapy failure Imatinib also acts as an inhibitor of CYP3A4 2C9 and 2D6 increasing the plasma concentrations of a number of other drugs like simvastatin ciclosporin pimozide warfarin metoprolol and possibly paracetamol The drug also reduces plasma levels of levothyroxin via an unknown mechanism 22 As with other immunosuppressants application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient Inactivated and toxoid vaccines do not hold this risk but may not be effective under imatinib therapy 28 Pharmacology EditMechanism of action Edit ImatinibDrug mechanism Crystallographic structure of tyrosine protein kinase ABL rainbow colored N terminus blue C terminus red complexed with imatinib spheres carbon white oxygen red nitrogen blue 29 Therapeutic usechronic myelogenous leukemiaBiological targetABL c kit PDGF RMechanism of actionTyrosine kinase inhibitorExternal linksATC codeL01XE01PDB ligand idSTI PDBe RCSB PDBLIGPLOT1iepImatinib is a 2 phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes It occupies the TK active site leading to a decrease in activity 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 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 constitutively active tyrosine kinase imatinib is used to decrease bcr abl activity The active sites of tyrosine kinases each have a binding site for ATP The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates a process known as protein tyrosine phosphorylation Imatinib works by binding close to the ATP binding site of bcr abl locking it in a closed or self inhibited conformation and therefore inhibiting the enzyme activity of the protein semi competitively 30 This fact explains why many BCR ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation 31 Imatinib is quite selective for bcr abl though it does also inhibit other targets mentioned above c kit and PDGF R as well as ABL2 ARG and DDR1 tyrosine kinases and NQO2 an oxidoreductase 32 Imatinib also inhibits the abl protein of non cancer cells but these cells normally have additional redundant tyrosine kinases which allows them to continue to function even if abl tyrosine kinase is inhibited Some tumor cells however have a dependence on bcr abl 33 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 leading to tumor cell death 34 Other pathways affected Edit The Bcr Abl pathway has many downstream pathways including 35 the Ras MapK pathway which leads to increased proliferation due to increased growth factor independent cell growth It also affects the Src Pax Fak Rac pathway This affects the cytoskeleton which leads to increased cell motility and decreased adhesion The PI PI3K AKT BCL 2 pathway is also affected BCL 2 is responsible for keeping the mitochondria stable this suppresses cell death by apoptosis and increases survival The last pathway that Bcr Abl affects is the JAK STAT pathway which is responsible for proliferation 35 Pharmacokinetics Edit Imatinib is rapidly absorbed when given by mouth and is highly bioavailable 98 of an oral dose reaches the bloodstream Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system including CYP3A4 and to a lesser extent CYP1A2 CYP2D6 CYP2C9 and CYP2C19 The main metabolite N demethylated piperazine derivative is also active The major route of elimination is in the bile and feces only a small portion of the drug 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 h and 40 h respectively It blocks the activity of Abelson cytoplasmic tyrosine kinase ABL c Kit and the platelet derived growth factor receptor PDGFR As an inhibitor of PDGFR imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases Imatinib has been reported to be an effective treatment for FIP1L1 PDGFRalpha mast cell disease hypereosinophilic syndrome and dermatofibrosarcoma protuberans 36 Chemistry EditSynthesis Edit History EditImatinib was invented in the late 1990s by scientists at Ciba Geigy which merged with Sandoz in 1996 to become Novartis in a team led by the British biochemist Nicholas Lydon and that included Elisabeth Buchdunger and Jurg Zimmermann 37 and its use to treat CML was driven by oncologist Brian Druker of Oregon Health amp Science University OHSU 38 Other major contributions to imatinib development were made by Carlo Gambacorti Passerini a physician scientist and hematologist at the University of Milano Bicocca Italy John Goldman at Hammersmith Hospital in London and later on by Charles Sawyers of Memorial Sloan Kettering Cancer Center in New York 38 39 Imatinib was developed by rational drug design After the Philadelphia chromosome mutation and hyperactive bcr abl protein were discovered the investigators screened chemical libraries to find a drug that would inhibit that protein With high throughput screening they identified 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 40 When Novartis tested imatinib in rats mice rabbits dogs and monkeys in 1996 it was found to have several toxic effects in particular results indicating liver damage in dogs nearly stopped drug development completely However favorable results in studies with monkeys and in vitro human cells allowed testing to continue in humans 41 42 43 The first clinical trial of Gleevec took place in 1998 after Novartis reluctantly synthesized and released a few grams of the drug for Druker enough for him to run a trial using a hundred or so patients 44 The drug received FDA approval in May 2001 only two and a half years after the new drug application was submitted 37 45 On the same month it made the cover of TIME magazine as a bullet to be used against cancer Druker Lydon and Sawyers received the Lasker DeBakey Clinical Medical Research Award in 2009 for converting a fatal cancer into a manageable chronic condition 38 During the FDA review the tradename of the drug for the US market was changed from Glivec to Gleevec at the request of the FDA to avoid confusion with Glyset a diabetes drug 46 47 48 A Swiss patent application was filed on imatinib and various salts on in April 1992 which was then filed in the EU the US and other countries in March and April 1993 49 50 and in 1996 United States and European patent offices issued patents listing Jurg Zimmermann as the inventor 49 51 In July 1997 Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate the mesylate salt of imatinib The beta crystalline form of the molecule is a specific polymorph of imatinib mesylate a specific way that the individual molecules pack together to form a solid This is the actual form of the drug sold as Gleevec Glivec a salt imatinib mesylate as opposed to a free base and the beta crystalline form as opposed to the alpha or other form 52 3 and 4 In 1998 Novartis filed international patent applications claiming priority to the 1997 filing 53 54 A United States patent was granted in 2005 55 Society and culture EditEconomics Edit A box of 400 milligram Glivec tablets Novartis as sold in Germany In 2013 more than 100 cancer specialists published a letter in Blood saying that the prices of many new cancer drugs including imatinib are so high that people in the United States couldn t afford them and that the level of prices and profits was so high as to be immoral Signatories of the letter included Brian Druker Carlo Gambacorti Passerini and John Goldman developers of imatinib 56 57 They wrote that in 2001 imatinib was priced at 30 000 equivalent to 45 911 in 2021 a year which was based on the price of interferon then the standard treatment and that at this price Novartis would have recouped its initial development costs in two years They wrote that after unexpectedly becoming a blockbuster Novartis increased the price to 92 000 equivalent to 108 589 in 2021 per year in 2012 with annual revenues of 4 7 billion Other physicians have complained about the cost 58 59 60 Druker who led the clinical studies never received any royalties or profits from the success of the drug 61 By 2016 the average wholesale price had increased to 120 000 equivalent to 135 491 in 2021 a year according to an analysis prepared for The Washington Post by Stacie Dusetzina of the University of North Carolina at Chapel Hill When competitive drugs came on the market they were sold at a higher price to reflect the smaller population clarification needed and Novartis raised the price of Gleevec to match them 62 A 2012 economic analysis funded by Bristol Myers Squibb estimated that the discovery and development of imatinib and related drugs had created 143 billion in societal value at a cost to consumers of approximately 14 billion The 143 billion figure was based on an estimated 7 5 to 17 5 year survival advantage conferred by imatinib treatment and included the value discounted at 3 per annum of ongoing benefits to society after the imatinib patent expiration 63 Prices for a 100 mg pill of Gleevec internationally range from 20 to 30 64 although generic imatinib is cheaper as low as 2 per pill 65 Controversies Edit Patent litigation in India Edit Main article Novartis v Union of India amp Others Novartis fought a seven year controversial battle to patent Gleevec in India and took the case all the way to the Indian Supreme Court The patent application at the center of the case was filed by Novartis in India in 1998 after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement As part of this agreement India made changes to its patent law the biggest of which was that prior to these changes patents on products were not allowed while afterwards they were albeit with restrictions These changes came into effect in 2005 so Novartis patent application waited in a mailbox with others until then under procedures that India instituted to manage the transition India also passed certain amendments to its patent law in 2005 just before the laws came into effect 66 67 The patent application 54 68 claimed the final form of Gleevec the beta crystalline form of imatinib mesylate 69 3 In 1993 during the time India did not allow patents on products Novartis had patented imatinib with salts vaguely specified in many countries but could not patent it in India 49 51 The key differences between the two patent applications were that 1998 patent application specified the counterion Gleevec is a specific salt imatinib mesylate while the 1993 patent application did not claim any specific salts nor did it mention mesylate and the 1998 patent application specified the solid form of Gleevec the way the individual molecules are packed together into a solid when the drug itself is manufactured this is separate from processes by which the drug itself is formulated into pills or capsules while the 1993 patent application did not The solid form of imatinib mesylate in Gleevec is beta crystalline 70 As provided under the TRIPS agreement Novartis applied for Exclusive Marketing Rights EMR for Gleevec from the Indian Patent Office and the EMR was granted in November 2003 71 Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India 72 73 When examination of Novartis patent application began in 2005 it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups The application was rejected by the patent office and by an appeal board The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005 describing the patentability of new uses for known drugs and modifications of known drugs That section 3d specified that such inventions are patentable only if they differ significantly in properties with regard to efficacy 72 74 At one point Novartis went to court to try to invalidate Section 3d it argued that the provision was unconstitutionally vague and that it violated TRIPS Novartis lost that case and did not appeal 75 Novartis did appeal the rejection by the patent office to India s Supreme Court which took the case The Supreme Court case hinged on the interpretation of Section 3d The Supreme Court issued its decision in 2013 ruling that the substance that Novartis sought to patent was indeed a modification of a known drug the raw form of imatinib which was publicly disclosed in the 1993 patent application and in scientific articles that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib and that therefore the patent application was properly rejected by the patent office and lower courts 76 Research EditOne study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis including those who had the D816V mutation in c KIT 77 However since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c KIT is constitutively active imatinib does not inhibit the kinase activity of the D816V mutant of c KIT Experience has shown however that imatinib is much less effective in patients with this mutation and patients with the mutation comprise nearly 90 of cases of mastocytosis Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes including portopulmonary hypertension 78 However a long term trial of Imatinib in people with pulmonary arterial hypertension was unsuccessful and serious and unexpected adverse events were frequent These included 6 subdural hematomas and 17 deaths during or within 30 days of study end 79 In systemic sclerosis the drug has been tested for potential use in slowing down pulmonary fibrosis In laboratory settings imatinib is being used as an experimental agent to suppress platelet derived growth factor PDGF by inhibiting its receptor PDGF Rb One of its effects is delaying atherosclerosis in mice without 80 or with diabetes 81 Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox should an outbreak ever occur 82 In vitro studies identified that a modified version of imatinib can bind to gamma secretase activating protein GSAP GSAP selectively increases the production and accumulation of neurotoxic beta amyloid plaques which suggests that molecules which target GSAP and are able to cross blood brain barrier are potential therapeutic agents for treating Alzheimer s disease 83 Another study suggests that imatinib may not need to cross the blood brain barrier to be effective at treating Alzheimer s as the research indicates the production of beta amyloid may begin in the liver Tests on mice indicate that imatinib is effective at reducing beta amyloid in the brain 84 It is not known whether reduction of beta amyloid is a feasible way of treating Alzheimer s as an anti beta amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms 85 A formulation of imatinib with a cyclodextrin Captisol as a carrier to overcome the blood brain barrier has shown reversal of opioid tolerance in a 2012 study in rats 86 Imatinib is an experimental drug in the treatment of desmoid tumor or aggressive fibromatosis medical citation needed Etymology EditThe tinib word stem makes reference to the drug s action as a tyrosine kinase TYK inhibitor 87 See also EditBcr Abl tyrosine kinase inhibitor History of cancer chemotherapyReferences Edit Imatinib Gleevec Use During Pregnancy Drugs com 27 August 2018 Retrieved 16 February 2020 a b c d e f g h i Imatinib Mesylate The American Society of Health System Pharmacists Archived from the original on 16 January 2017 Retrieved 8 January 2017 Green KN Crapser JD Hohsfield LA September 2020 To Kill a Microglia A Case for CSF1R Inhibitors Trends in Immunology 41 9 771 784 doi 10 1016 j it 2020 07 001 PMC 7484341 PMID 32792173 Mun SH Park PS Park Min KH August 2020 The M CSF receptor in 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