a small-molecule inhibitor
Imatinib mesylate (also called Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia.
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.
Description
In May 2001, the FDA approved imatinib as a new cancer drug after a record review
time of just 2.5 months. Imatinib was launched as Gleevec in the US for chronic
myelogenous leukemia (CML) in blast crisis, accelerated phase or chronic phase after interferon-alpha failure. This compound can be prepared by a four step sequence from a
condensation of the 1-(3-pyridyl)ethanone with dimethyl formamide dimethylacetal,
followed by successive cyclization with the methyl-nitrophenyl guanidine, hydrogenolysis
and condensation with the benzoyl chloride of the methylpiperazine. Imatinib is the first of
a new class of anticancer drugs that are specifically designed to target the molecular
pathways involved (oncogenic event) in the development of disease. The Brc-Abl
oncoprotein is a constitutively active tyrosine kinase that causes CML. Imatinib is a
competitive inhibitor of this tyrosine kinase as well as Abl, Kit and the PDGFR kinases It
binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate
from ATP to the tyrosine residues of various substrates and consequently blocks the
proliferation of the leukemic cells. Phase II studies demonstrated that in chronic phase
CML, over 90% of the patients had their leukocyte counts return to normal and 56% had a
major cytogenic response. No phase III data is currently available. It is clear from the
evidence available that imatinib has advantages over IFN-alpha, such as reduced toxicity,
more rapid hematological response, higher rate of cytogenic response and oral
administration. The drug is well tolerated, producing few side effects, classified as grade 1
nausea, muscle cramps, diarrhea, edema and vomiting. Imatinib is metabolized primarily
by the CYP3A4 enzyme system and drugs capable of modulating this system would be
expected to modify the patient's exposure. Novartis expects to launch imatinib for the
treatment of gastrointestinal stromal tumors in 2002.
Chemical Properties
Off-White Solid
Originator
Novartis (Switzerland)
Uses
Imatinib Mesylate (STI571) is an orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively.
Uses
Imatinib Mesylate is orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively. Imatinib also known as Gleevec, Glivec, CGP-57148B, STI-571 & Imatinib
Uses
A tyrosine kinase inhibitor. Highly specific for BCR-ABL, the enzyme associated with chronic myelogenous leukemia (CML) and certain forms of acute lymphoblastic leukemia (ALL)
Uses
echinocandin antifungal, active against infections with Aspergillus and Candida, inhibits cell wall synthesis
Definition
ChEBI: A methanesulfonate (mesylate) salt that is the monomesylate salt of imatinib. Used for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours.
brand name
Gleevec, Glivec
General Description
Imatinib is available in 100- and 400-mg capsules for oraladministration and is indicated for the treatment of CML,gastrointestinal stromal tumors (GIST) that express Kit andacute lymphoplastic leukemia that is positive for thePhiladelphia chromosome.
Bioavailability of the agent is nearly 100% by the oralroute. The agent is highly protein bound and metabolized tothe N-desmethyl derivative by CYP3A4-mediated removalof the piperazinyl methyl group. The resulting metabolite issimilar to the parent in activity. Elimination occurs primarilyin the feces, and the terminal half-life is 18 hours forthe parent and 40 hours of the N-desmethyl metabolite.Resistant forms of the TK are known, which have alteredamino acids that prevent binding. In addition, there may beincreased levels of the kinase itself. The drug is also a substratefor Pgp and an additional efflux transporter known asbreast cancer resistance protein (BCRP), both of which removethe drug from the cell. These transporters are also inhibitedby the agent as well. Severe side effects include ascites,neutropenia, thrombocytopenia, skin rash, andpulmonary edema. Less serious side effects include nausea/vomiting, heartburn, and headache but overall, the agentis better tolerated than most other medications used in treatingthe disease.
Biochem/physiol Actions
Imatinib mesylate is a tyrosine kinase inhibitor with antineoplastic activity. Imatinib is a potent inhibitor of the Bcr-Abl kinase encoded by the bcr-abl oncogene as well as receptor tyrosine kinases encoded by c-kit and platelet-derived growth factor receptor (PDGFR) oncogenes. Imatinib mesylate inhibition of Bcr-Abl tyrosine kinase created by the Philadelphia chromosome abnormality found in CML decreases proliferation and enhances apoptosis in leukemias CML and ALL. Inhibition of c-kit tyrosine activity inhibits mast-cell and cellular proliferation in those diseases overexpressing c-kit such as gastrointestinal stromal tumor (GIST).
References
1) Buchdunger, et al.(1996) Inhibition of the Abl Protein-Tyrosine Kinase in Vitro and in Vivo by a 2-Phenylpyrimidine Derivative; Cancer Res. 56 100
2) Heinrich et al (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96 925
3) Morioka et al. (2016) Effect of Collagen Type 1 or Human Fibronectin on Imatinib Cytotoxicity in Oral Squamous Cell Carcinoma; Pharmacology and Pharmacy, 7 255 [Focus Biomolecules Citation]
4) Hazekawa et al. (2017) Assessment of cytotoxicity of imatinib for oral squamous cell carcinoma by a real-time cell analysis system; E. J. Bio., 13 56 [ Focus Biomolecules Citation]
