Reddy E Premkumar, Aggarwal Aneel K
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA.
Genes Cancer. 2012 May;3(5-6):447-54. doi: 10.1177/1947601912462126.
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.
针对Abl的抑制剂的研发改变了慢性粒细胞白血病（CML）以及总体癌症的治疗格局。从伊马替尼用于CML的重大发现及获批开始，第二代抑制剂尼洛替尼和达沙替尼现已获批用于CML的治疗。值得注意的是，这些第二代抑制剂对Abl激酶中许多赋予对伊马替尼耐药性的突变具有活性。然而，耐药性仍然是一个主要问题，并且已经开发出了如普纳替尼和GNF2/GNF5等新型抑制剂，它们对常见的守门人T315I突变具有活性。我们在此综述Abl抑制的机制，重点关注对新分子的选择性和设计很重要的结构元件。特别地，我们聚焦于Abl的P环、激活环、DFG模体及其他结构元件的构象变化如何有助于理解抑制剂结合。
