Systemic Therapy
Imatinib - Mechanism of Action
Glivec is an orally available member of the 2-phenylaminopyrimidine class of small molecules that were rationally designed to competitively bind to the ATP-binding pocket of specific tyrosine kinases1.
Glivec competitively inhibits ATP from binding to the nucleotide binding pocket of specific tyrosine kinase receptors, including KIT (see Figure 1) and PDGFR. Competitive inhibition prevents the transfer of phosphate groups from ATP to tyrosine residues on substrate proteins, referred to as phosphorylation. This selectivity for KIT and PDGFR, which are present in malignant GISTs, results in inhibition of cell proliferation and restoration of apoptosis2,3. KIT mutations are common in GIST and, together with PDGFRA mutations, predict efficacy of Glivec therapy.
Figure 1: Glivec binding to specific tyrosine kinase receptors2,3
Glivec inhibits members of the class 3 family of receptor tyrosine kinases at micromolar concentrations, including KIT, the receptor for SCF, PDGFRα and PDGFRβ4. Additionally, Glivec inhibits ABL and BCR-ABL at concentrations in the micromolar range in vitro5. Glivec has also been shown to inhibit macrophage colony-stimulating factor receptor c-Fms4,6. ARG, another cytoplasmic protein-tyrosine kinase structurally related to ABL, is also inhibited by Glivec (Table 1)7.
| Inhibited Kinases | Kinases Not Inhibited | |
|---|---|---|
| BCR-ABL | EGFR-RICD | v-Scr |
| v-Abl | Her-2/neu | c-Fgr |
| c-Abl | Insulin receptor | Fit-1 |
| Tel-Abl | IGF-I-R | Tek |
| PDGFRα | c-Lyn | c-Met |
| PDGFRβ | Fit-3 | PPK |
| Tel-PDGFR | Kdr | |
| KIT | Jak-2 | |
| Arg | TPK | |
| cFMS | cScr | |
References:
1. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343-3356.
2. D'Amato G, Steinert DM, McAuliffe JC, Trent JC. Update on the biology and therapy of gastrointestinal stromal tumors. Cancer Control. 2005;12:44-56.
3. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-187.
4. Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000;295:139-145.
5. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100-104.
6. Dewar AL, Cambareri AC, Zannettino AC, et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood. 2005;105:3127-3132.
7. Okuda K, Weisberg E, Gilliland DG, Griffin JD. ARG tyrosine kinase activity is inhibited by STI571. Blood. 2001;97:2440-2448.