AMN107的特性，一种天然和突变型Bcr-Abl的选择性抑制剂。

Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.

作者信息

Weisberg Ellen, Manley Paul W, Breitenstein Werner, Brüggen Josef, Cowan-Jacob Sandra W, Ray Arghya, Huntly Brian, Fabbro Doriano, Fendrich Gabriele, Hall-Meyers Elizabeth, Kung Andrew L, Mestan Jürgen, Daley George Q, Callahan Linda, Catley Laurie, Cavazza Cara, Azam Mohammad, Neuberg Donna, Wright Renee D, Gilliland D Gary, Griffin James D

机构信息

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

出版信息

Cancer Cell. 2005 Feb;7(2):129-41. doi: 10.1016/j.ccr.2005.01.007.

DOI:10.1016/j.ccr.2005.01.007

PMID:15710326

Abstract

The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.

摘要

Bcr-Abl酪氨酸激酶致癌基因可引发慢性粒细胞白血病（CML）以及费城染色体阳性（Ph+）急性淋巴细胞白血病（ALL）。我们描述了一种新型的Bcr-Abl选择性抑制剂AMN107（IC50<30 nM），其效力显著高于伊马替尼，并且对多种伊马替尼耐药的Bcr-Abl突变体具有活性。Abl-AMN107复合物的晶体学分析为AMN107和伊马替尼针对伊马替尼耐药Bcr-Abl的差异活性提供了结构上的解释。与其体外和药代动力学特征一致，AMN107延长了注射Bcr-Abl转化造血细胞系或原代骨髓细胞的小鼠的生存期，并延长了伊马替尼耐药CML小鼠模型的生存期。AMN107是一种有前景的用于治疗CML和Ph+ ALL的新型抑制剂。