Allosteric inhibitors of Bcr-abl-dependent cell proliferation
Allosteric inhibitors of Bcr-abl-dependent cell proliferation
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DOI：
10.1038/nchembio760
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发表时间：
2006-02-01
影响因子：
14.8
通讯作者：
Gray, NS
中科院分区：
文献类型：
--
作者：
Adrián, FJ;Ding, Q;Gray, NS
慢性粒细胞白血病（CML）是一种骨髓增生性疾病，其特征在于在分子水平上表达Bcr-abl，一种210-kDa的融合蛋白，具有失调的酪氨酸激酶活性。Bcr-abl作为伊马替尼治疗CML的靶点的临床验证鼓舞了我们，我们试图确定可以通过不同机制靶向这种激酶的药理学药物。我们报告发现一类新的Bcr-abl抑制剂使用无偏差分细胞毒性筛选的组合激酶指导的杂环库。这类化合物（以GNF-2为例）对Bcr-abl转化的细胞显示出独有的抗增殖活性，其效力与伊马替尼相似，但对c-abl全长或催化结构域的激酶活性无抑制作用。我们认为这类新化合物通过变构非ATP竞争机制抑制Bcr-abl激酶活性。
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class ( exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.