Binding or Bending: Distinction of Allosteric Abl Kinase Agonists from Antagonists by an NMR-Based Conformational Assay

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• 作者：Wolfgang Jahnke ; Robert M. Grotzfeld ; Xavier Pell ; Andr Strauss ; Gabriele Fendrich ; Sandra W. Cowan-Jacob ; Simona Cotesta ; Doriano Fabbro ; Pascal Furet ; Jrgen Mestan ; Andreas L. Marzinzik
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：May 26, 2010
• 年：2010
• 卷：132
• 期：20
• 页码：7043-7048
• 全文大小：265K
• 年卷期：v.132,no.20(May 26, 2010)
• ISSN：1520-5126

文摘

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.