Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay

…, A Strauss, G Fendrich, SW Cowan-Jacob…

Index: Jahnke, Wolfgang; Grotzfeld, Robert M.; Pelle, Xavier; Strauss, Andre; Fendrich, Gabriele; Cowan-Jacob, Sandra W.; Cotesta, Simona; Fabbro, Doriano; Furet, Pascal; Mestan, Juergen; Marzinzik, Andreas L. Journal of the American Chemical Society, 2010 , vol. 132, # 20 p. 7043 - 7048

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Citation Number: 49

Abstract

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 ...