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Cancer Res. 2012 Oct 1;72(19):4890-5. doi: 10.1158/0008-5472.CAN-12-1276. Epub 2012 Sep 21.

The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL.

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1
École Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.

Abstract

The BCR-ABL fusion kinase is the driving mutation of chronic myelogenous leukemias and is also expressed in a subset of acute lymphoblastic leukemias. Recent advances in elucidating the structure, regulation, and signaling of BCR-ABL have led to the identification of allosteric sites that are distant from the ATP-binding pocket and are critical for BCR-ABL-dependent oncogenic transformation. Here, we review the available data regarding the molecular mechanism of action and the specificity of ATP-competitive tyrosine kinase inhibitors targeting BCR-ABL. In addition, we discuss how targeting of allosteric sites could provide new opportunities to inhibit resistant BCR-ABL mutants, either alone or in combination with conventional ATP-competitive inhibitors.

PMID:
23002203
PMCID:
PMC3517953
DOI:
10.1158/0008-5472.CAN-12-1276
[Indexed for MEDLINE]
Free PMC Article
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