Nilotinib: A Novel, Selective Tyrosine Kinase Inhibitor

被引:119
作者
Blay, Jean-Yves [2 ]
von Mehren, Margaret [1 ]
机构
[1] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA
[2] Univ Lyon 1, Ctr Leon Berard, Dept Med, F-69365 Lyon, France
关键词
IN-VITRO ACTIVITY; GIANT-CELL TUMOR; IMATINIB-RESISTANT; BCR-ABL; C-KIT; AMN107; MESYLATE; MUTATION; PDGFRA; TRANSPORT;
D O I
10.1053/j.seminoncol.2011.01.016
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The development of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myelogenous leukemia (CML) was based on the discovery that CML stem and progenitor cells overexpress the abnormal fusion protein kinase BCR-ABL. The prototype TKI, imatinib, selectively inhibits BCR-ABL, as well as several other kinases, including stem cell factor receptor (KIT), discoidin domain receptor (DDR), platelet-derived growth factor receptor (PDGFR), and colony-stimulating factor receptor-1 (CSF-1R). Although the management of CML improved dramatically with the introduction of imatinib, not all patients benefit from treatment because of resistance or intolerance. Consequently, research efforts have focused on developing more potent TKIs with the ability to circumvent imatinib resistance. Nilotinib, a second-generation oral TXI, was rationally designed based on the crystal structure of imatinib to be highly active against a wide range of imatinib-resistant BCR-ABL mutants and is approved for the treatment of newly diagnosed or imatinib-resistant or -intolerant CML, and has shown superiority over imatinib in first-line treatment for newly diagnosed CML. Furthermore, the activity of nilotinib against KIT and PDGFR alpha has led to its evaluation in advanced gastrointestinal stromal tumors (GIST). The purpose of this review is to describe the development of nilotinib, providing a structural explanation for the differential activity of nilotinib and imatinib in GIST. Activity of nilotinib against KIT and PDGFR and emerging evidence of differences in cellular uptake between nilotinib and imatinib are discussed. Semin Oncol 38 (Suppl 1):S3-S9 (c) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:S3 / S9
页数:7
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