Gleevecs Effects on tryosine Kinase

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 was originally coded during development as CGP57148B or STI-571 (these terms are used in early preclinical publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.

The animation begins by introducing the Philadelphia Chromosome, the result of a reciprocal translocation between chromosomes 9 and 22. More specifically the breakpoint cluster region (BCR) of chromosome 22 is fused with part of the Abelson (ABL) gene on chromosome 9. The resulting BCR-ABL genetic domain now located within chromosome 22 and codes for a mutant tyrosine kinase also known as BCR-ABL. Under normal circumstances tyrosine kinase proteins respond to external cellular messaging proteins, and ultimately initiate a series of reactions that culminate in cellular replication.

Conversely, BCR-ABL is constitutively active, meaning it does not require activation by the aforementioned cellular messaging proteins in order to stimulate cellular replication. This results in acceleration of cell division, an inhibition of DNA repair, overall genomic instability, and the fatal blast crisis characteristic of chronic myelogenous leukemia. The animation progresses to introduce Gleevec (imatinib), the first in a class of drugs that specifically target and competively inhibit the ATP binding site on BCR-ABL tyrosine kinase. This prevents the ABL domain from phosphorylating the tyrosine residue, and as a result preventing the proliferation of hematopoietic cells that express BCR-ABL. Therapy with imatinib results in a dramatic reduction of tumor clone cells and the occurrence of blast crisis', through targeted drug treatment which leaves health cells unscathed.