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

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.

SUBMITTER: Hantschel O

PROVIDER: S-EPMC3517953 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Hantschel Oliver O Grebien Florian F Superti-Furga Giulio G

Cancer research 20120921 19

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 ...[more]

PMID: 23002203

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