Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl
Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl
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DOI：
10.1016/j.ccr.2005.01.007
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发表时间：
2005-02-01
期刊：
影响因子：
50.3
通讯作者：
Griffin, JD
中科院分区：
文献类型：
--
作者：
Weisberg, E;Manley, PW;Griffin, JD
Bcr-Abl酪氨酸激酶癌基因引起慢性髓细胞性白血病（CML）和费城染色体阳性（Ph+）急性淋巴细胞性白血病（ALL）。我们描述了一种新的选择性Bcr-Abl抑制剂AMN 107（IC 50 < 30 nM），它比伊马替尼更有效，并且对许多伊马替尼耐药的betacr-Abl突变体有活性。AMN-AMN 107复合物的晶体学分析为AMN 107和伊马替尼对伊马替尼耐药Bcr-Abl的差异活性提供了结构解释。与其体外和药代动力学特征一致，AMN 107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。AMN 107是一种很有前途的治疗CIVIL和Ph+ ALL的新型抑制剂。
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 betacr-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 CIVIL and Ph+ ALL.