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

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 t...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2010-05, Vol.132 (20), p.7043-7048
Main Authors: Jahnke, Wolfgang, Grotzfeld, Robert M, Pellé, Xavier, Strauss, André, Fendrich, Gabriele, Cowan-Jacob, Sandra W, Cotesta, Simona, Fabbro, Doriano, Furet, Pascal, Mestan, Jürgen, Marzinzik, Andreas L
Format: Article
Language:English
Subjects:
Allosteric Regulation
Animals
Drug Evaluation, Preclinical - methods
Enzyme Activation - drug effects
Humans
Ligands
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Myristic Acid - metabolism
Protein Binding
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Protein Structure, Secondary
Proto-Oncogene Proteins c-abl - agonists
Proto-Oncogene Proteins c-abl - antagonists & inhibitors
Proto-Oncogene Proteins c-abl - chemistry
Proto-Oncogene Proteins c-abl - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja101837n