Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
J Am Chem Soc. 2010 May 26;132(20):7043-8. doi: 10.1021/ja101837n.
Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.
变构 Bcr-Abl 抑制剂已成为治疗 CML 的一种新的治疗选择。使用基于片段的筛选，进行了寻找与豆蔻酸口袋结合的新型 Abl 抑制剂的研究。在这里，我们表明并非所有豆蔻酸配体都是功能性抑制剂，而是 C 端螺旋_I 的构象状态是功能活性的结构决定因素。我们提出了一种基于 NMR 的构象测定法来监测该关键螺旋_I 的构象，并表明使螺旋_I 弯曲的豆蔻酸配体是功能性拮抗剂，而结合到豆蔻酸口袋但不诱导这种构象变化的配体则是激酶激动剂。在生化测定中已证实变构激动剂激活 c-Abl。
