Imatinib- Glivec
Mechanism of Action
Glivec is a member of the 2-phenylaminopyrimidine class of small molecules that has high affinity and selectivity for ABL (Figure 1).1-4 Protein kinases, including ABL, contain within their catalytical domain a nucleotide-binding pocket and an activation loop, which controls activity. While the nucleotide-binding pocket among kinases is highly conserved, the molecular shapes of the activation loop in inactive kinases are diverse.5,6 Glivec, which binds to the ABL nucleotide-binding pocket, recognises and stabilises a distinctive inactive conformation of the activation loop of ABL and precludes ATP binding (Figure 2). Glivec prevents BCR-ABL from phosphorylating tyrosine residues of substrate proteins, thereby interrupting BCR-ABL signal transduction pathways that lead to leukaemic transformation. Although Glivec also inhibits wild-type ABL, it does not affect normal signal transduction pathways, presumably because of redundant signalling. No clinical evidence of inhibition of normal processes has been observed with Glivec therapy.
Figure 1. Nucleotide binding pocket.
Figure 2. Glivec binding explained.
Click on the image to enlarge
In addition to inhibiting ABL and BCR-ABL at concentrations in the micromolar range in vitro,7 Glivec has also been shown to inhibit members of the class 3 family of receptor protein-tyrosine kinases: platelet-derived growth factor receptor-alpha (PDGFRα); PDGFRβ; KIT, the receptor for stem-cell factor or steel factor; and macrophage colony-stimulating factor receptor c-Fms.1, 4, 7-10 ARG, another cytoplasmic protein-tyrosine kinase structurally related to ABL, is also inhibited by Glivec (Table 1).11
| Kinases Inhibited | 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 | |
| c-KIT | Jak-2 | |
| Arg | TPK | |
| cFMS | cScr | |
References:
1. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
2. Deininger MW, Goldman JM, Lydon N, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691-3698.
3. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394.
4. 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.
5. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289:1938-1942.
6. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002;62:4236-4243.
7. Glivec Summary of Product Characteristics [SMPC]. Basel, Switzerland: Novartis Pharma AG; 2006.
8. 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.
9. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 2002;20:1692-1703.
10. 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.
11. Okuda K, Weisberg E, Gilliland DG, Griffin JD. ARG tyrosine kinase activity is inhibited by STI571. Blood. 2001;97:2440-2448.