The ins and outs of bcr-abl inhibition.
The ins and outs of bcr-abl inhibition.
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DOI：
10.1177/1947601912462126
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发表时间：
2012-05-01
期刊：
影响因子：
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通讯作者：
Aggarwal, Aneel K
中科院分区：
文献类型：
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作者：
Reddy, E Premkumar;Aggarwal, Aneel K
针对Abl的抑制剂的开发已经改变了慢性粒细胞白血病（CML）和癌症的总体治疗前景。从伊马替尼治疗CML的重大发现和批准开始，第二代抑制剂尼洛替尼和达沙替尼现已获得批准用于治疗CML。值得注意的是，这些第二代抑制剂对Abl激酶中赋予伊马替尼耐药性的许多突变具有活性。然而，耐药性仍然是一个主要问题，已经开发了新的抑制剂，如泊那替尼和GNF 2/GNF 5，对常见的看门人T315 I突变具有活性。在这里，我们回顾了Abl抑制的机制，重点是对新分子的选择性和设计很重要的结构元素。特别是，我们专注于如何在构象的P-环，激活环，DFG基序，和其他结构元素的Abl的变化一直有助于发展抑制剂结合的理解。
The development of inhibitors against Abl has changed the landscape for the treatment of chronic myelogenous leukemia (CML) and cancer in general. Beginning with the monumental discovery and approval of imatinib for CML, a second generation of inhibitors, nilotinib and dasatinib, has now gained approval for the treatment of CML. Notably, these second-generation inhibitors are active against many of the mutations in the Abl kinase that confer resistance to imatinib. However, resistance remains a major problem, and new inhibitors such as ponatinib and GNF2/GNF5 have been developed, with activity towards the common gatekeeper T315I mutation. We review here the mechanisms of Abl inhibition with an emphasis on structural elements that are important for the selectivity and design of new molecules. In particular, we focus on how changes in the conformation of the P-loop, the activation loop, the DFG motif, and other structural elements of Abl have been instrumental in developing an understanding of inhibitor binding.