page_title: Imatinib
section_title: Mechanism of action
hierarchical_section_title: Imatinib / Mechanism of action
caption_attribution_description: English: Crystallographic structure of Imatinib (STI-571) complexed with the proto-oncogene tyrosine-protein kinase ABL based on PDB 1IEP
context_page_description: Imatinib, sold under the brand name Gleevec among others, is an oral chemotherapy medication used to treat cancer. Specifically, it is used for chronic myelogenous leukemia and acute lymphocytic leukemia that are Philadelphia chromosome-positive, certain types of gastrointestinal stromal tumors, hypereosinophilic syndrome, chronic eosinophilic leukemia, systemic mastocytosis, and myelodysplastic syndrome. It is taken by mouth.
  Common side effects include vomiting, diarrhea, muscle pain, headache, and rash. Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure. Use during pregnancy may result in harm to the baby. Imatinib works by stopping the Bcr-Abl tyrosine-kinase. This can slow growth or result in programmed cell death of certain types of cancer cells.
  Imatinib was approved for medical use in the United States in 2001. It is on the World Health Organization's List of Essential Medicines. A generic version became available in the UK as of 2017.
context_section_description: 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. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
  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. 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. 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.
caption: 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).[24]
exif: {}