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          Institute: MPI für molekulare Physiologie     Collection: Abteilung IV - Chemische Biologie     Display Documents



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ID: 611010.0, MPI für molekulare Physiologie / Abteilung IV - Chemische Biologie
Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl
Authors:Schneider, Ralf; Becker, Christian; Simard, Jefrrey R.; Getlik, Matthäus; Bohlke, Nina; Janning, Petra; Rauh, Daniel
Date of Publication (YYYY-MM-DD):2012-06-06
Title of Journal:Journal of the American Chemical Society
Volume:134
Issue / Number:22
Start Page:9138
End Page:9141
Sequence Number of Article:1
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Jürgen Block
Affiliations:MPI für molekulare Physiologie/Abteilung IV - Chemische Biologie/AG Dr. Petra Janning
MPI für molekulare Physiologie/Chemical Genomics Center of the MPS /AG Dr. Daniel Rauh
Identifiers:URL:http://dx.doi.org/10.1021/ja303858w [Article locator with full text links]
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