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Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl

MPS-Authors

Schneider,  Ralf
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98679

Becker,  Christian
Abt. III: Physikalische Biochemie, Max Planck Institute of Molecular Physiology, Max Planck Society;

Simard,  Jefrrey R.
Max Planck Institute of Molecular Physiology, Max Planck Society;

Getlik,  Matthäus
Max Planck Institute of Molecular Physiology, Max Planck Society;

Bohlke,  Nina
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98701

Janning,  Petra
Abt. IV: Chemische Biologie, Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98721

Rauh,  Daniel
Chemical Genomics Center of the MPS, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Citation

Schneider, R., Becker, C., Simard, J. R., Getlik, M., Bohlke, N., Janning, P., et al. (2012). Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl. Journal of the American Chemical Society, 134(22): 1, pp. 9138-9141. Retrieved from http://dx.doi.org/10.1021/ja303858w.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0013-FED9-0
Abstract
Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.