Chronic Myeloid Leukemia Knowledge Centre

Nilotinib- Tasigna ®

Preclinical Studies

In preclinical studies, nilotinib inhibited phosphorylation of wild-type BCR-ABL in vitro at concentrations in the nanomolar range (Table 1).1,2 Nilotinib also inhibits proliferation of cells expressing BCR-ABL at >20-fold lower concentrations compared with imatinib (Figure 1).3,4,5 One study attributed the antiproliferative activity of nilotinib in cells to enhanced expression of proapoptotic proteins.6

Table 1. The IC 50 for Nilotinib Inhibition of Kinase phoshorylation in Vitro 10
20 nM 69 nM 210 nM

Nilotinib has demonstrated antileukemic activity in animal models.3,7 Mice with similar tumor burden, as a consequence of injection with bone-marrow cells expressing BCR-ABL, were treated with nilotinib or vehicle. After 4 doses, administered once daily, there was a 1-log reduction in overall tumor burden in nilotinib-treated mice compared with a 1.5-log increase in tumor burden in vehicle-treated mice (Figure 2).3 Survival was also prolonged in nilotinib-treated mice bearing leukemic cells compared with similar mice treated with vehicle.3,7

In addition to inhibition of proliferation of cells expressing wild-type BCR-ABL, nilotinib also inhibits proliferation of cells expressing each of 32 among 33 tested imatinib-resistant BCR-ABL mutants (Figure 3).3, 4,2,8 Cells expressing the T315I mutant were not inhibited by nilotinib. The T315 residue is positioned to serve as the “gatekeeper,” thus a substitution by the large amino acid isoleucine causes a conformational readjustment of the protein that interferes with nilotinib binding.9 The T315I substitution also prohibits binding of imatinib and dasatinib to BCR-ABL.10,11

The potential spectrum of BCR-ABL mutants likely to result in Tasigna resistance in patients has been explored in cell-based screening experiments.12,13 All mutants arising under these experimental conditions, excluding T315I, could be inhibited in vitro by nilotinib concentrations that can be achieved in the plasma of patients treated with therapeutic doses of Tasigna. These preclinical experiments suggest only a small spectrum of BCR-ABL mutations is likely to give rise to Tasigna resistance in patients. Nilotinib was designed to be highly specific for BCR-ABL, but also inhibits tyrosine kinase activity of the stem-cell-factor receptor KIT, PDGFRa, and PDGFRb with potency similar to that of imatinib.3 Ephrin receptor kinases are inhibited by nilotinib at concentrations within the range achieved in serum of patients treated with Tasigna® at therapeutic doses.1

Nilotinib has no significant effect on other kinases evaluated including SRC, FLT3, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), insulin receptor (InsR), RET, MET, and insulin-related growth factor receptor (IGFR)3 (Figures 1 and 4).14,15


Figure 1. Comparison of IC 50 for Nilotinib or Imatinib Inhibition of Cell Proliferation6,10.

Comparison of IC 50 for Nilotinib or Imatinib Inhibition of Cell Proliferation6,10

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Figure 2. Efficacy of Nilotinib in Mice With Leukemia 6.

Efficacy of Nilotinib in Mice With Leukemia 6

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Figure 3. Nilotinib Sensitivity of Cells Expressing Imatinib-Resistant BCR-ABL Amino-acid.

Nilotinib Sensitivity of Cells Expressing Imatinib-Resistant BCR-ABL Amino-acid

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Figure 4. Nilotinib Targets in Human Kinome Dendrogram 66,67

Nilotinib Targets in Human Kinome Dendrogram 66,67

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1. Tasigna® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis; 2007.
2. Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94:1765-1769.
3. 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.
4. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505.
5. Tasigna® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis; 2007.
6. 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.
7. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11:4941-4947.
8. Cowan-Jacob SW, Guez V, Fendrich G, et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem. 2004;4:285-299.
9. Pricl S, Fermeglia M, Ferrone M, Tamborini E. T315Imutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study. Mol Cancer Ther. 2005;4:1167-1174.
10. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640-2653.
11. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.
12. Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood. 2006;108:2332-2338.
13. Von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. 2006;108:1328-1333.
14. Fabian MA, Biggs WH, 3rd, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23:329-336.
15. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912-1934.

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