Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically bcrabl, ckit, and pdgfra. Imatinibglivec in pediatric cml patients with complete molecular. Imatinib binds to the the atp binding site of the enzyme. Its development is an excellent example of rational drug design.
The mechanism of action of imatinib in the present patient is merely speculative. Bcrabl is an ideal target for molecular targeted therapy, because this fusion protein is present in all of the cml cells, is absent from nonmalignant cells, and is necessary and sufficient to induce leukemia. The following conditions are contraindicated with this drug. Besides the previously described antiproliferative effects, which might have caused the longterm clinical improvement, vasodilation might have played a role as well, although such an effect of imatinib on the pulmonary vasculature has not been described. These harbor kit mutations and produce ligandindependent constitutive activation of kit 300,301. Understanding the molecular basis of imatinib mesylate. It prevents a bcrabl protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia cml.
Scientific discussion this module reflects the initial. In addition, imatinib blocks the plateletderived growth. Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Longterm outcomes of imatinib treatment for chronic. It is best to read this with our information about the type of cancer you have.
A under physiological conditions, atp binds to kit or pdgfra, leading to phosphorylation and autoactivation of the receptor, or phosphorylation of substrate molecules resulting in activation of downstream signalling pathways. Patient information for imatinib devatis 400 mg filmcoated tablets including dosage instructions and possible side effects. Possible role of imatinib in clinical pulmonary veno. International recommendations to discontinue imatinib. Mechanism of action imatinib is a small molecule proteintyrosine kinase inhibitor that potently inhibits the activity of the bcrabl tyrosine kinase tk, as well as several receptor tks. Tasigna is a better topological fit than imatinib for the kinasebinding domain 3 with superior efficacy vs imatinib. In adults, it is used for disease that has recurred come back or is refractory does not respond to treatment. Imatinib suppresses activation of egfr tyrosine kinase. Check with your physician if you have any of the following.
While imatinib decreases survivin expressions to some extent, combination with a compound that can further decrease survivin could further increase imatinibs ability to kill cancer cells. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions interactions recommended clinical monitoring supplementary public funding references disclaimer. In children, it is used with chemotherapy as the first treatment after the disease is diagnosed. Imatinib is an inhibitor of multiple tyrosine kinases including ckit, abl, scf and pdgfr. Imatinib is rapidly absorbed orally and is highly bioavailable. Imatinib is now the treatment of choice for most newly diagnosed patients. Imatinib, sold under the brand name gleevec among others, is a medication used to treat. Practical management of patients with chronic myeloid. Mechanism of action imatinib mesylate is a proteintyrosine kinase inhibitor that inhibits the bcrabl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the philadelphia chromosome abnormality in chronic myeloid leukemia cml. Imatinib fine mechanisms of action had been elucidated to rationally develop those second and thirdgeneration inhibitors.
Therefore, the authors evaluated the efficacy and safety of imatinib mesylate as treatment for patients with systemic mastocytosis. It inhibits proliferation and induces apoptosis in bcrabl positive cell lines. Highlights of prescribing information these highlights do not include all the information needed to use gleevec safely and effectively. Imatinib inhibits bcrabl tyrosine kinase, the fusion protein created by the philadelphia chromosome abnormality that characterizes chronic myeloid leukemia. Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the abl tyrosine kinases, including bcrabl. Imatinib inhibits bcrabl tyrosine kinase, the fusion protein created by the philadelphia chromosome abnormality. Imatinib interrupts kitmediated signal transduction in a manner similar to inhibition of bcrabl and. The biochemical mechanism of action was confirmed in the. While imatinib decreases survivin expressions to some extent, combination with a compound that can further decrease survivin could further increase imatinib s ability to kill cancer cells. Imatinib exerts is mechanism of action through competitive inhibition at the atpbinding site of the bcrabl protein, which results in inhibition of phosphorylation of proteins involved in cell signal transduction. Imatinib is a small molecule proteintyrosine kinase inhibitor that potently inhibits the activity of the. Imatinib was the first signal transduction inhibitor sti, used in a clinical setting. P webmd including its uses, side effects and safety, interactions, pictures, warnings and user ratings. On012380, a putative bcrabl kinase inhibitor with a.
Crystallographic structure of tyrosineprotein kinase abl rainbow colored, nterminus blue, cterminus red complexed with imatinib spheres, carbon white, oxygen red, nitrogen blue. Optical activity imatinib mesylate does not have chiral centers, and it is not optically active. Kit, the receptor for stem cell factor scf coded for by the ckit proto oncogene, the discoidin. Indeed, a superior antiatherosclerotic action of imatinib in the abdominal region versus aortic arch was also reported in ldlsmooth muscle lrp1 knockout mice. As the mechanism of action of imatinib is to inhibit the bcrabltyrosine kinase, it would seem likely that to achieve maximum therapeutic bene. However, the action of imatinib is a bit different in case of gist. Imatinib directly inhibits the constitutive tyrosine kinase activity.
Imatinib mesylate is a proteintyrosine kinase inhibitor that inhibits the bcrabl tyrosine kinase, the constitutive abnormal tyrosine kinase. A copy of the license is included in the section entitled gnu free documentation license. Smyth,7 8 and guido kroemer3,5 6 9 10 1inserm, u1015, 94805 villejuif, france 2center of clinical investigations cbt507 3metabolomics and cell biology platforms institut gustave roussy, 94805 villejuif, france. Imatinib is specific for the tk domain in abl the abelson protooncogene, ckit and pdgfr. Imatinib directly prevents metabolism of egfr tyrosine kinase. Imatinib was identified in the late 1990s by dr brian j. International drug price indicator guide 2014 edition pdf. Tyrosine kinases are proteins in the body that control how cells grow and divide. A breakthrough of targeted therapy in cancer ncbi nih. Apart from its remarkable success in cml and gist, imatinib benefits various other tumors caused by imatinibspecific abnormalities of pdgfr and ckit.
Cml is caused by an abnormal chromosomal translocation that results in the formation of the bcrabl fusion protein. Proof of concept in the clinical setting was demonstrated by the high response rates seen in a phase i study. It is used to treat some types of leukaemia, blood disorders and cancers. Imatinib mesylate is a smallmolecule tyrosine kinase inhibitor that was initially developed as a 2phenylaminopyrimidine derivative specific for pdgfr. After nearly 11 years of followup, longterm administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have e. The drug imatinib mesylate that blocks the receptor tyrosine kinase activity responsible for initiation of signaling was recently commercialized for therapy nimmanapalli and bhalla, 2002. Sunitinib was recently approved in firstline treatment for patients with advanced renal cell carcinoma rcc and for the treatment of patients with gastrointestinal stromal tumors gist after disease progression or intolerance to imatinib mesylate therapy. Patients with systemic mastocytosis received imatinib mesylate orally at a dose of 400 mg once daily for 3 to 6 months. Imatinib was subsequently found to be a potent inhibitor of abl kinases.
Mechanisms of disease chronic myeloid leukemia advances in biology. Several mechanisms of resistance to imatinib in gist have been. Imatinib was one of the first cancer therapies to show the potential for such targeted action. A concise, flowbased synthesis of imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed. Imatinib also inhibits the receptor tyrosine kinases for platelet derived growth factor pdgf and stem cell factor scf called ckit. Excellent responses, in terms of symptom control and haematological parameters, are usually obtained.
Acute lymphoblastic leukemia in adults and children that is philadelphia chromosome positive. Imatinib attenuates diabetesassociated atherosclerosis. Mechanism of action of bcrabl and of its inhibition by imatinib. Permission is granted to copy, distribute andor modify this document under the terms of the gnu free documentation license, version 1. On012380, a putative bcrabl kinase inhibitor with a unique mechanism of action in imatinibresistant cells. Gleevec imatinib mesylate tablets, for oral use initial u. Reinstating immunosurveillance laurence zitvogel,1,2 4 11lorenzo galluzzi,5 6 mark j. It should be noted that the mechanism of action for imatinib mesylate appears to depend on inhibition of bcrabls antiapoptotic. Imatinib suppresses activation of bcrabl tyrosine kinase. Mechanism of action imatinib is a small molecule proteintyrosine kinase inhibitor that potently inhibits the. The umcg and poitiers will act as a coordination unit for the database and exchange of. This fusion protein is present in up to 95% of patients with this disease. The product of the bcrabl gene is a kinase that adds phosphate groups onto target molecules substrates. Soon after identification of the bcrabl target, the search for an inhibitor.
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