Nilotinib: a novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance.
Although high rates of complete hematologic and cytogenetic remission have been observed in patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib, a short duration of response with eventual emergence of imatinib resistance has also been reported in a subset of CML patients. The most frequent clinically relevant mechanisms that change imatinib sensitivity in BCR-ABL-transformed cells are mutations within the Abl kinase domain, affecting several of its properties. Crystal structure analysis of the Abl-imatinib complex has proven helpful in identifying potential critical residues that hinder interactions of imatinib with mutated Abl. This has led to the development of a second generation of targeted therapies such as nilotinib and dasatinib, already in phase II clinical trials or SKI-606 and MK-0457 in phase I trials. In this review, we discuss the activity of nilotinib, developed by Novartis using a rational drug design strategy in which imatinib served as the lead compound. Preliminary studies demonstrated that nilotinib has more efficacy than imatinib in inhibiting proliferation of BCR-ABL-dependent cells, a relatively safety profile and clinical efficacy in all phases of CML.
Martinelli
Giovanni
G
Institute of Hematology and Medical Oncology "Seràgnoli", University of Bologna, Bologna, Italy.
Iacobucci
Ilaria
I
Soverini
Simona
S
Palandri
Francesca
F
Castagnetti
Fausto
F
Rosti
Gianantonio
G
Baccarani
Michele
M
Blood. 2007 Jan 15;109(2):500-2
16990603
Mini Rev Med Chem. 2004 Mar;4(3):285-99
15032675
Blood. 2006 Sep 15;108(6):1835-40
16709931
Clin Cancer Res. 2005 Jul 1;11(13):4941-7
16000593
Blood. 2006 Jul 15;108(2):697-704
16597591
Clin Cancer Res. 2006 Dec 1;12(23):7180-6
17145844
Blood. 2004 Dec 15;104(13):4245-51
15319292
Semin Hematol. 2003 Apr;40(2 Suppl 2):26-30
12783372
Blood. 2002 Jan 15;99(2):664-71
11781252
Cancer Res. 2005 Jun 1;65(11):4500-5
15930265
J Clin Oncol. 2006 Jan 20;24(3):454-9
16421422
Blood. 2006 Sep 15;108(6):1809-20
16709930
Clin Cancer Res. 2006 Dec 15;12(24):7374-9
17189410
Br J Cancer. 2006 Jun 19;94(12):1765-9
16721371
Blood. 2004 Oct 1;104(7):1979-88
15198956
N Engl J Med. 2006 Dec 7;355(23):2408-17
17151364
Hematology Am Soc Hematol Educ Program. 2006;:219-25
17124064
Leuk Lymphoma. 2006 Jan;47(1):1-7
16321820
Blood. 2007 Apr 15;109(8):3207-13
17185463
Blood. 2002 May 1;99(9):3472-5
11964322
Cancer Cell. 2002 Aug;2(2):117-25
12204532
Blood. 2007 Jan 15;109(2):497-9
16990591
Blood. 2003 Jul 1;102(1):276-83
12623848
J Clin Oncol. 2005 Jun 20;23(18):4100-9
15867198
Curr Opin Genet Dev. 2006 Feb;16(1):92-9
16343892
Blood. 2007 Mar 15;109(6):2303-9
17138817
Cancer Res. 2006 Feb 15;66(4):2279-86
16489032
J Mass Spectrom. 2006 Mar;41(3):390-404
16470567
Mol Cancer Ther. 2005 Aug;4(8):1167-74
16093432
Cancer. 2005 Sep 15;104(6):1230-6
16078266
Methods Mol Med. 2006;125:93-106
16502579
Cancer Res. 2005 Jun 15;65(12):5358-64
15958584
Leukemia. 2003 Dec;17(12):2392-400
14523462
N Engl J Med. 2005 Jul 14;353(2):172-87
16014887
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1992-7
15677719
Hematology Am Soc Hematol Educ Program. 2005;:183-7
16304378
N Engl J Med. 2003 Oct 9;349(15):1423-32
14534335
N Engl J Med. 2006 Jun 15;354(24):2531-41
16775234
N Engl J Med. 2001 Apr 5;344(14):1031-7
11287972
Leukemia. 2002 Nov;16(11):2190-6
12399961
N Engl J Med. 2006 Jun 15;354(24):2542-51
16775235
Semin Hematol. 2003 Apr;40(2 Suppl 2):69-79
12783379
Leuk Lymphoma. 2006 Sep;47(9):1768-73
17064986
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11011-6
16046538