Allosteric inhibitors of Bcr-abl–dependent cell proliferation


Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl–transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

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Figure 1: Cell proliferation.
Figure 2: GNF-2 blocks proliferation and induces apoptosis of Ba/F3 cells expressing wild-type Bcr-abl and the E255V mutant.
Figure 3: Construct-dependent inhibition of abl activity by GNF-2.
Figure 4: GNF-2 binds recombinant abl and Bcr-abl.
Figure 5: Model of GNF-2 bound to the abl crystal structure (PDB entry 1OPK).

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We thank J.D. Griffin, G. Gilliland, R. Salgia and J. Duyster for kindly providing us with cell lines, and C. Trussell, D. Kemp, M. Warmuth and S. Kim for their help and valuable discussions.

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Correspondence to Nathanael S Gray.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Inhibition of cell proliferation. (PDF 19 kb)

Supplementary Table 2

Inhibition of in vitro kinase activity. (PDF 68 kb)

Supplementary Methods (PDF 41 kb)

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Adrián, F., Ding, Q., Sim, T. et al. Allosteric inhibitors of Bcr-abl–dependent cell proliferation. Nat Chem Biol 2, 95–102 (2006).

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