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

Jahnke, Wolfgang and Grotzfeld, Robert and Pelle, Xavier and Strauss, Andre and Fendrich, Gabriele and Jacob, Sandra and Cotesta, Simona and Fabbro, Doriano and Furet, Pascal and Mestan, Juergen and Marzinzik, Andreas (2010) Binding or bending: Distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. Journal of the American Chemical Society, 130 (20). pp. 7043-7048.

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 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.

Item Type: Article
Additional Information: archiving not formally supported by this publisher
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2420

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