Nilotinib - Tasigna®
Mechanism of Action
BCR-ABL tyrosine kinase inhibitor
The active component of Tasigna, nilotinib, is a novel aminopyrimidine that binds to the adenosine triphosphate binding site of BCR-ABL and inhibits phosphotransferase activity of the BCR-ABL tyrosine kinase (Figure 1).1,2,3 The chemical structure of nilotinib was based on imatinib with the intent of enhancing inhibitory activity and specificity for BCR-ABL relative to imatinib (Figure 2).1
Figure 1. Mechanism of Action of Nilotinib (Tasigna) 4,5.
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Figure 2. Chemical Structure of Nilotinib and Imatinib.
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Similar to imatinib, nilotinib binds to the unconserved inactive conformation of BCR-ABL (Figure 3).1 Interruption of BCR-ABL signaling cascades in leukemic cells with nilotinib ultimately leads to decreased cell proliferation and promotion of apoptosis.3
Figure 3. Three-dimensional Representation of Nilotinib (A) Bound to BCR-ABL (B), and Comparison of Nilotinib and Imatinib Binding Surfaces to Human ABL (C)1
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References:
1. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141.
2. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-57 inhibition of abelson tyrosine kinase. Science. 2000;289:1938-1942.
3. Aichberger KJ, Mayerhofer M, Krauth MT, et al. Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia: role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds. Cancer Res. 2005;65:9436-9444.
4. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767-1773.
5. Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with
imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611-4614.